Pharmacokinetics, pharmacodynamics, safety and tolerability of an intravaginal ring releasing anastrozole and levonorgestrel in healthy premenopausal women: a Phase 1 randomized controlled trial.

PubMed

Schultze-Mosgau, M-H; Waellnitz, K; Nave, R; Klein, S; Kraetzschmar, J; Rautenberg, T; Schmitz, H; Rohde, B

2016-08-01

What are suitable doses of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG), when delivered to the systemic circulation by an intravaginal ring (IVR), for further clinical development as a potential new therapy for the treatment of endometriosis? Anticipated targets for pharmacokinetics, pharmacodynamics and safety/tolerability were achieved for both drug components of the IVR at the doses investigated, supporting selection of the doses to be investigated in Phase 2 studies. Aromatase is a key enzyme in the biosynthesis of estrogens and is known to increase local levels of estradiol (E2) at extragonadal sites. Up-regulation of aromatase expression has been demonstrated in endometriotic lesions and the use of oral aromatase inhibitors has been shown to reduce endometriosis-associated pelvic pain in small-scale clinical trials. This Phase 1, randomized, multicentre, parallel-group, three-arm, open-label study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of various IVRs intended for systemic drug delivery. After screening, healthy, ovulating women aged 18-35 years were randomized to use IVRs releasing one of the three ATZ/LNG dose combinations (in vitro nominal daily drug release rates on Day 29: ATZ/LNG 500 µg/20 µg [low dose], ATZ/LNG 1000 µg/30 µg [mid dose] or ATZ/LNG 1500 µg/40 µg [high dose]) for two consecutive 28-day wearing periods without a treatment break. Sixty women were included in the per protocol set. The primary variables were plasma concentrations of ATZ and LNG at the end of each treatment period and the mean size of largest follicle-like structures (FLSs) over 56 days. Serum concentrations of several hormones were also evaluated, with emphasis on E2 levels. At the end of the first treatment period, geometric mean plasma concentrations of LNG and ATZ, respectively, were 0.228 and 12.5 µg/l for the low dose, 0.269 and 19.8 µg/l for the mid dose and 0.384 and 37.3 µg/l for the high

Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor.

PubMed

Herman, Ann E; Chinn, Leslie W; Kotwal, Shweta G; Murray, Elaine R; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian P; Hanze, Eva L; Viberg, Anders; Morimoto, Alyssa M; Winter, Helen R; Katsumoto, Tamiko R

2018-06-01

GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications. © 2018 American Society for Clinical Pharmacology and Therapeutics.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

PubMed Central

2012-01-01

Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies. PMID:22340283

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world post-marketing surveillance data.

PubMed

Kawamura, Takahisa; Kasai, Hidefumi; Fermanelli, Valentina; Takahashi, Toshiaki; Sakata, Yukinori; Matsuoka, Toshiyuki; Ishii, Mika; Tanigawara, Yusuke

2018-06-22

Post-marketing surveillance is useful to collect safety data in real-world clinical settings. In this study, we firstly applied the post-marketing real-world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer (RBC/MBC). Demographic and safety data were collected using an active surveillance method from eribulin-treated RBC/MBC patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that may affect the severity of neutropenia were investigated and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h -1 , neutrophil elimination rate constant = 0.0295 h -1 , and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of post-marketing surveillance data to a model-based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency.

PubMed

Cohen-Barak, Orit; Sakov, Anat; Rasamoelisolo, Michele; Bassan, Merav; Brown, Kurt; Mendzelevski, Boaz; Spiegelstein, Ofer

2015-11-01

TV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy. To assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers. Subjects (n=56) were assigned to one of seven ascending dose groups (3-100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection. Eighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23-35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose. Single administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD. © 2015 The authors.

Safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus: Results from a phase 1/2 randomized study.

PubMed

Tsuru, Tomomi; Tanaka, Yoshiya; Kishimoto, Mitsumasa; Saito, Kazuyoshi; Yoshizawa, Seiji; Takasaki, Yoshinari; Miyamura, Tomoya; Niiro, Hiroaki; Morimoto, Shinji; Yamamoto, Junichi; Lledo-Garcia, Rocio; Shao, Jing; Tatematsu, Shuichiro; Togo, Osamu; Koike, Takao

2016-01-01

This 12-week, randomized, double-blind, placebo-controlled, multicenter phase 1/2 study (NCT01449071) assessed the safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus despite standard of care. Twenty patients were randomized 1:1:1:1:1 to placebo or one of four epratuzumab dose regimens (100 mg every other week [Q2W], 400 mg Q2W, 600 mg every week [QW], or 1200 mg Q2W) administered during an initial 4-week dosing period. Adverse events (AEs), pharmacokinetics and pharmacodynamics were assessed. Nineteen of 20 patients completed the study. All placebo patients and 13 of 16 epratuzumab patients reported ≥1 AE, 2 of 16 epratuzumab patients reported a serious AE. C(max) and AUC(τ) increased proportionally with dose after first and last infusion, t(1/2) was similar across groups (∼13 days). Epratuzumab treatment was associated with decreased CD22 mean fluorescence intensity in total B cells (CD19(+)CD22(+)) and unswitched memory B cells (CD19(+)IgD(+)CD27(+)). Small-to-moderate decreases were observed in total B cell (CD20(+)) count. Epratuzumab was well-tolerated, with no new safety signals identified. The pharmacokinetics appeared linear after first and last infusions. Treatment with epratuzumab was associated with CD22 downregulation and with small-to-moderate decreases in total B cell count.

Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

PubMed

Kast, Johannes; Yu, Yichao; Seubert, Christoph N; Wotring, Virginia E; Derendorf, Hartmut

2017-11-15

Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight. Copyright © 2017 Elsevier B.V. All rights reserved.

Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.

PubMed

Mahalingam, Devalingam; Mita, Monica; Sarantopoulos, John; Wood, Leslie; Amaravadi, Ravi K; Davis, Lisa E; Mita, Alain C; Curiel, Tyler J; Espitia, Claudia M; Nawrocki, Steffan T; Giles, Francis J; Carew, Jennifer S

2014-08-01

We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.

Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog.

PubMed

Knudsen, T; Kristensen, A T; Nichols, T C; Agersø, H; Jensen, A L; Kjalke, M; Ezban, M; Tranholm, M

2011-11-01

Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti-human FVIIa antibodies develop (~2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over-expressed by gene transfer in haemophilia dogs, has provided long-term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg(-1) to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half-life (FVIIa activity: 1.2-1.8 h; FVIIa antigen 2.8-3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin-activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans. © 2011 Blackwell Publishing Ltd.

Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults.

PubMed

Min, Sherene; Sloan, Louis; DeJesus, Edwin; Hawkins, Trevor; McCurdy, Lewis; Song, Ivy; Stroder, Richard; Chen, Shuguang; Underwood, Mark; Fujiwara, Tamio; Piscitelli, Stephen; Lalezari, Jay

2011-09-10

To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of dolutegravir (DTG), a next-generation HIV integrase inhibitor (INI), as short-term monotherapy. A phase IIa, randomized, double-blind, dose-ranging study. In this study, INI-naive, HIV-1-infected adults currently off antiretroviral therapy were randomized to receive DTG (2, 10, or 50 mg) or placebo once daily for 10 days in an eight active and two placebo randomization scheme per DTG dose. Placebo patients were pooled for the purpose of analysis. Thirty-five patients (n = 9 for DTG 2 and 10 mg, n = 10 for DTG 50 mg, and n = 7 for placebo) were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all DTG dose groups compared with placebo (P < 0.001), with a mean decrease of 1.51-2.46 log(10) copies/ml. In addition, a well characterized dose-response relationship was observed for viral load decrease. Most patients (seven of 10, 70%) receiving DTG 50 mg achieved plasma HIV-1 RNA less than 50 copies/ml. The pharmacokinetic variability was low (coefficient of variation, range 25-50%). Plasma HIV-1 RNA reduction was best predicted by Cτ using an E(max) model. The most common adverse events were diarrhea, fatigue, and headache; the majority of adverse events were mild or moderate in severity. Dolutegravir demonstrated potent antiviral activity, good short-term tolerability, low pharmacokinetic variability, and a predictable pharmacokinetics/pharmacodynamics relationship, which support once-daily dosing without a pharmacokinetic booster in integrase-naive patients in future studies.

A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload.

PubMed

Rienhoff, Hugh Young; Viprakasit, Vip; Tay, Lay; Harmatz, Paul; Vichinsky, Elliott; Chirnomas, Deborah; Kwiatkowski, Janet L; Tapper, Amy; Kramer, William; Porter, John B; Neufeld, Ellis J

2011-04-01

There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (C(max)) was reached within 60-90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t(1/2)) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419).

Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia.

PubMed

Fleischmann, Roy; Kerr, Bradley; Yeh, Li-Tain; Suster, Matt; Shen, Zancong; Polvent, Elizabeth; Hingorani, Vijay; Quart, Barry; Manhard, Kimberly; Miner, Jeffrey N; Baumgartner, Scott

2014-12-01

The aim of this study was to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of lesinurad (selective uric acid reabsorption inhibitor) in combination with febuxostat (xanthine oxidase inhibitor) in patients with gout. This study was a phase IB, multicentre, open-label, multiple-dose study of gout patients with serum uric acid (sUA) >8 mg/dl following washout of urate-lowering therapy with colchicine flare prophylaxis. Febuxostat 40 or 80 mg/day was administered on days 1-21, lesinurad 400 mg/day was added on days 8-14 and then lesinurad was increased to 600 mg/day on days 15-21. sUA, urine uric acid and PK profiles were evaluated at the end of each week. Safety was assessed by adverse events, laboratory tests and physical examinations. Initial treatment with febuxostat 40 or 80 mg/day monotherapy resulted in 67% and 56% of subjects, respectively, achieving a sUA level <6 mg/dl. Febuxostat 40 or 80 mg/day plus lesinurad 400 or 600 mg/day resulted in 100% of subjects achieving sUA <6 mg/dl and up to 100% achieving sUA <5 mg/dl. No clinically relevant changes in the PKs of either drug were noted. The combination was well tolerated. The clinically important targets of sUA <6 mg/dl and <5 mg/dl are achievable in 100% of patients when combining lesinurad and febuxostat. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics-Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose.

PubMed

Struys, Michel M R F; Valk, Beatrijs I; Eleveld, Douglas J; Absalom, Anthony R; Meyer, Peter; Meier, Sascha; den Daas, Izaak; Chou, Thomas; van Amsterdam, Kai; Campagna, Jason A; Sweeney, Steven P

2017-07-01

Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.

Comparable pharmacodynamics, efficacy, and safety of linagliptin 5 mg among Japanese, Asian and white patients with type 2 diabetes.

PubMed

Sarashina, Akiko; Friedrich, Christian; Crowe, Susanne; Patel, Sanjay; Graefe-Mody, Ulrike; Hayashi, Naoyuki; Horie, Yoshiharu

2016-09-01

The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase-4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials. Study 1 (with a 12-week placebo-controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24-week trial) enrolled Asian (non-Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90). Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half-maximal inhibitory concentration, resulting in dipeptidyl peptidase-4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase-4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non-Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group. Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non-Japanese) and white patients, confirming that the recommended 5-mg once-daily dose of linagliptin is appropriate for use among different race groups. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Safety, pharmacokinetics and pharmacodynamics of the anti‐hepcidin Spiegelmer lexaptepid pegol in healthy subjects

PubMed Central

Boyce, M; Warrington, S; Cortezi, B; Zöllner, S; Vauléon, S; Swinkels, D W; Summo, L; Schwoebel, F

2016-01-01

Background and Purpose Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l‐oligoribonucleotide, binds and inactivates hepcidin. Experimental Approach We conducted a placebo‐controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg−1. Key Results After treatment with lexaptepid, serum iron concentration and transferrin increased dose‐dependently. Iron increased from approximately 20 μmol·L−1 at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg−1 lexaptepid. The pharmacokinetics showed dose‐proportional increases in peak plasma concentrations and moderately over‐proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti‐drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg−1 and with local injection site reactions after s.c. but not after i.v. administration. Conclusions and Implications Lexaptepid pegol inhibited hepcidin and dose‐dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease. PMID:26773325

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

PubMed

Palmer, Melissa; Jennings, Lee; Silberg, Debra G; Bliss, Caleb; Martin, Patrick

2018-03-16

Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990�

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

PubMed Central

Solmi, Marco; Murru, Andrea; Pacchiarotti, Isabella; Undurraga, Juan; Veronese, Nicola; Fornaro, Michele; Stubbs, Brendon; Monaco, Francesco; Vieta, Eduard; Seeman, Mary V; Correll, Christoph U; Carvalho, André F

2017-01-01

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed

Offset of pharmacodynamic effects and safety of remifentanil in intensive care unit patients with various degrees of renal impairment

PubMed Central

Breen, Des; Wilmer, Alexander; Bodenham, Andrew; Bach, Vagn; Bonde, Jan; Kessler, Paul; Albrecht, Sven; Shaikh, Soraya

2004-01-01

Introduction This open label, multicentre study was conducted to assess the times to offset of the pharmacodynamic effects and the safety of remifentanil in patients with varying degrees of renal impairment requiring intensive care. Methods A total of 40 patients, who were aged 18 years or older and had normal/mildly impaired renal function (estimated creatinine clearance ≥ 50 ml/min; n = 10) or moderate/severe renal impairment (estimated creatinine clearance <50 ml/min; n = 30), were entered into the study. Remifentanil was infused for up to 72 hours (initial rate 6–9 μg/kg per hour), with propofol administered if required, to achieve a target Sedation–Agitation Scale score of 2–4, with no or mild pain. Results There was no evidence of increased offset time with increased duration of exposure to remifentanil in either group. The time to offset of the effects of remifentanil (at 8, 24, 48 and 72 hours during scheduled down-titrations of the infusion) were more variable and were statistically significantly longer in the moderate/severe group than in the normal/mild group at 24 hours and 72 hours. These observed differences were not clinically significant (the difference in mean offset at 72 hours was only 16.5 min). Propofol consumption was lower with the remifentanil based technique than with hypnotic based sedative techniques. There were no statistically significant differences between the renal function groups in the incidence of adverse events, and no deaths were attributable to remifentanil use. Conclusion Remifentanil was well tolerated, and the offset of pharmacodynamic effects was not prolonged either as a result of renal dysfunction or prolonged infusion up to 72 hours. PMID:14975051

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.

PubMed

Wang, Xiaoli; Tirucherai, Giridhar; Marbury, Thomas C; Wang, Jessie; Chang, Ming; Zhang, Donglu; Song, Yan; Pursley, Janice; Boyd, Rebecca A; Frost, Charles

2016-05-01

An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in apixaban concentration. A single 5-mg oral dose of apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on apixaban clearance. © 2015, The American College of Clinical Pharmacology.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.

PubMed

Li, Xiaojiao; Liu, Chang; Wu, Min; Zhang, Hong; Sun, Yanfu; Cheng, Longmei; Chen, Hong; Liu, Chengjiao; Yang, Lizhi; Zhang, Qi; Cao, Yuchen; Gu, Jingkai; Ding, Yanhua

2016-08-01

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

Lubiprostone: pharmacokinetic, pharmacodynamic, safety and regulatory aspects in the treatment of constipation-predominant irritable bowel syndrome.

PubMed

Raschi, Emanuel; De Ponti, Fabrizio

2014-02-01

Lubiprostone acts locally (apical membrane of human intestinal epithelial cells) as a highly selective type-2 chloride channel activator. It was approved in the USA for chronic idiopathic constipation (January 2006) and in women aged ≥ 18 years suffering from irritable bowel syndrome with constipation (IBS-C) (April 2008). So far, the only other pro-secretory medication approved in IBS-C and currently available in USA and Europe (since August and November 2012, respectively) is linaclotide. This review outlines the regulatory history, pharmacokinetic, pharmacodynamic and safety data in the treatment of IBS-C with a European perspective. It is based on publicly available data, namely, published literature, drug labels and the FDA's spontaneous reporting system. Although interesting pharmacodynamic data suggest that lubiprostone may have additional mechanisms of action, its beneficial effects in IBS-C must be confirmed in the actual clinical scenario taking into account the new version of European Medicines Agency's guideline. This is especially important with regard to duration of studies (recommended to be at least 6 months) to adequately assess long-term sustained efficacy, withdrawal, rebound and safety. Further research is warranted in uncertain areas (i.e., males, pediatric and elderly patients). On the basis of current data, it is still too early to draw definite conclusions on the overall risk-benefit balance for IBS-C.

A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor.

PubMed

Tsai, Max; Chrones, Lambros; Xie, Jinhui; Gevorkyan, Hakop; Macek, Thomas A

2016-10-01

Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum. Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study. Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort). The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max =  6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs. TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.

Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder.

PubMed

Ragguett, Renee-Marie; Rong, Carola; Rosenblat, Joshua D; Ho, Roger C; McIntyre, Roger S

2018-04-01

Treatment resistant depression (TRD) represents approximately 20% of all individuals receiving care for major depressive disorder. The opioidergic system is identified as a novel target which hitherto has not been sufficiently investigated in adults with TRD. The combination product buprenorphine + samidorphan is an opioid modulatory agent which has demonstrated replicated evidence of efficacy in TRD without abuse liability. Areas covered: Databases Pubmed, Google Scholar and clinicaltrials.gov were searched from inception through December 2017 for clinical trial information, pharmacokinetics, and pharmacodynamics of buprenorphine + samidorphan. Herein we provide a summary of the available information. Eight clinical trials were identified for inclusion, of the eight trials, five trials had available results and are included in detail in our review. Expert opinion: Buprenorphine + samidorphan has demonstrated efficacy in TRD. Extant evidence surrounding the safety and tolerability profile of buprenorphine + samidorphan does not identify any significant safety concerns. Additional studies are needed in order to assess the long-term safety and efficacy of this product.

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects.

PubMed

Miller, Ann K; Harrell, Emma; Ye, Li; Baptiste-Brown, Sharon; Kleim, Jőrg-Peter; Ohrt, Colin; Duparc, Stephan; Möhrle, Jörg J; Webster, Alison; Stinnett, Sandra; Hughes, Arlene; Griffith, Sandy; Beelen, Andrew P

2013-12-01

The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects. © 2013 The British Pharmacological Society.

Differential pharmacodynamic effects of paclitaxel formulations in an intracranial rat brain tumor model.

PubMed

Zhou, Rong; Mazurchuk, Richard V; Tamburlin, Judith H; Harrold, John M; Mager, Donald E; Straubinger, Robert M

2010-02-01

Nano- and microparticulate carriers can exert a beneficial impact on the pharmacodynamics of anticancer agents. To investigate the relationships between carrier and antitumor pharmacodynamics, paclitaxel incorporated in liposomes (L-pac) was compared with the clinical standard formulated in Cremophor-EL/ethanol (Cre-pac) in a rat model of advanced primary brain cancer. Three maximum-tolerated-dose regimens given by intravenous administration were investigated: 50 mg/kg on day 8 (d8) after implantation of 9L gliosarcoma tumors; 40 mg/kg on d8 and d15; 20 mg/kg on d8, d11, and d15. Body weight change and neutropenia were assessed as pharmacodynamic markers of toxicity. The pharmacodynamic markers of antitumor efficacy were increase in lifespan (ILS) and tumor volume progression, measured noninvasively by magnetic resonance imaging. At equivalent doses, neutropenia was similar for both formulations, but weight loss was more severe for Cre-pac. No regimen of Cre-pac extended survival, whereas L-pac at 40 mg/kg x2 doses was well tolerated and mediated 26% ILS (p < 0.0002) compared with controls. L-pac at a lower cumulative dose (20 mg/kg x3) was even more effective (40% ILS; p < 0.0001). In striking contrast, the identical regimen of Cre-pac was lethal. Development of a novel semimechanistic pharmacodynamic model permitted quantitative hypothesis testing with the tumor volume progression data, and suggested the existence of a transient treatment effect that was consistent with sensitization or "priming" of tumors by more frequent L-pac dosing schedules. Therefore, improved antitumor responses of carrier-based paclitaxel formulations can arise both from dose escalation, because of reduced toxicity, and from novel carrier-mediated alterations of antitumor pharmacodynamic effects.

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

PubMed Central

Frost, Charles; Nepal, Sunil; Wang, Jessie; Schuster, Alan; Byon, Wonkyung; Boyd, Rebecca A; Yu, Zhigang; Shenker, Andrew; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; LaCreta, Frank

2013-01-01

Aim Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. Method This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). Results Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile. Conclusion Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures. PMID:23451769

Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma.

PubMed

Yau, Thomas; Cheng, Paul N; Chan, Pierre; Chen, Li; Yuen, Jimmy; Pang, Roberta; Fan, Sheung Tat; Wheatley, Denys N; Poon, Ronnie T

2015-04-01

This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90%) were hepatitis B carriers. Median age was 61.5 (range 30-75). Overall disease control rate was 13%, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95% CI: 1.67-1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95% CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25%) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.

Critical factors and paths influencing construction workers' safety risk tolerances.

PubMed

Wang, Jiayuan; Zou, Patrick X W; Li, Penny P

2016-08-01

While workers' safety risk tolerances have been regarded as a main reason for their unsafe behaviors, little is known about why different people have different risk tolerances even when confronting the same situation. The aim of this research is to identify the critical factors and paths that influence workers' safety risk tolerance and to explore how they contribute to accident causal model from a system thinking perceptive. A number of methods were carried out to analyze the data collected through interviews and questionnaire surveys. In the first and second steps of the research, factor identification, factor ranking and factor analysis were carried out, and the results show that workers' safety risk tolerance can be influenced by four groups of factors, namely: (1) personal subjective perception; (2) work knowledge and experiences; (3) work characteristics; and (4) safety management. In the third step of the research, hypothetical influencing path model was developed and tested by using structural equation modeling (SEM). It is found that the effects of external factors (safety management and work characteristics) on risk tolerance are larger than that of internal factors (personal subjective perception and work knowledge & experiences). Specifically, safety management contributes the most to workers' safety risk tolerance through its direct effect and indirect effect; while personal subjective perception comes the second and can act as an intermedia for work characteristics. This research provides an in-depth insight of workers' unsafe behaviors by depicting the contributing factors as shown in the accident causal model developed in this research. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.

PubMed

Hurwitz, Herbert I; Smith, David C; Pitot, Henry C; Brill, Jeffrey M; Chugh, Rashmi; Rouits, Elisabeth; Rubin, Joseph; Strickler, John; Vuagniaux, Gregoire; Sorensen, J Mel; Zanna, Claudio

2015-04-01

To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects

PubMed Central

Miller, Ann K; Harrell, Emma; Ye, Li; Baptiste-Brown, Sharon; Kleim, Jőrg-Peter; Ohrt, Colin; Duparc, Stephan; Möhrle, Jörg J; Webster, Alison; Stinnett, Sandra; Hughes, Arlene; Griffith, Sandy; Beelen, Andrew P

2013-01-01

Aims The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Methods Healthy subjects, 18–55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1–2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. Results The coadministration of CQ + TQ had no effect on TQ AUC0–t, AUC0–∞, Tmax or t1/2. The 90% confidence intervals of CQ + TQ vs. TQ for AUC0–t, AUC0–∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0–24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. Conclusions No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects. PMID:23701202

Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.

PubMed

Jiao, Hui-Wen; Sun, Lu-Ning; Li, Yue-Qi; Yu, Lei; Zhang, Hong-Wen; Wang, Mei-Feng; Yu, Li-Yuan; Yuan, Zi-Qing-Yun; Xie, Li-Jun; Chen, Juan; Meng, Ling; Zhang, Xue-Hui; Wang, Yong-Qing

2018-03-01

The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.

First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics

PubMed Central

Hoesley, Craig J.; Plagianos, Marlena; Hoskin, Elena; Zhang, Shimin; Teleshova, Natalia; Alami, Mohcine; Novak, Lea; Kleinbeck, Kyle R.; Katzen, Lauren L.; Zydowsky, Thomas M.; Fernández-Romero, José A.; Creasy, George W.

2016-01-01

Objective: To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. Design: A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. Methods: Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose–response inhibition analysis. Results: Participants (n = 20) ranged from 19–44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti–herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. Conclusions: PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti–human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted

Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety.

PubMed

Sultana, Janet; Spina, Edoardo; Trifirò, Gianluca

2015-06-01

Antidepressants (ADs) are widely used among elderly persons, making AD-related safety an important issue. This review highlights safety considerations related to AD use including risks associated with inappropriate and off-label use. The age-related pharmacokinetic and pharmacodynamic changes underlying safety concerns connected to ADs are outlined. Drug-drug interactions as a cause of AD-related adverse drug reactions (ADRs) are also discussed. We reviewed scientific evidence concerning three important safety outcomes related to ADs in elderly persons: cardiac arrhythmias, hyponatraemia and falls/fractures. Several AD-related ADRs in elderly people are likely to be preventable. Current evidence suggests that selective serotonin re-uptake inhibitors (SSRIs) are best avoided particularly in persons with kidney disease due to the risk of hyponatraemia. The use of tricyclic antidepressants (TCAs) should be limited in the elderly due to anticholinergic adverse effects. TCAs should also be avoided in elderly persons at high risk of cardiovascular events due to a risk of cardiac arrhythmia. Emerging evidence suggests that SSRIs also have arrhythmogenic potential. Both TCAs and SSRIs should be used cautiously in elderly persons at risk of falls. Future research in this area should aim to investigate the lowest effective dose of AD possible, the relationship between AD dose and adverse effects, and which elderly subgroups are most prone to develop severe ADRs.

Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Piragliatin, a Glucokinase Activator, and Glyburide, a Sulfonylurea, in Type 2 Diabetic Patients.

PubMed

Zhai, S; Georgy, A; Liang, Z; Zhi, J

2016-11-01

A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose-lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open-label, multiple-dose, 3-period, single-sequence crossover design: on days -1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments. The glucose-lowering effect, including fasting plasma glucose (FPG), of piragliatin was more pronounced when it was administered concomitantly with glyburide as compared to piragliatin or glyburide administered alone. However, this enhancement cannot be explained by a potential PK interaction between piragliatin and glyburide. Other than hypoglycemia, there were no clinically relevant safety findings. Thus, the enhanced PD effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy, safety, and tolerability. © 2016, The American College of Clinical Pharmacology.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.

PubMed

Payne, Christopher D; Deeg, Mark A; Chan, Melanie; Tan, Lai Hock; LaBell, Elizabeth Smith; Shen, Tong; DeBrota, David J

2014-12-01

The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. © 2014 The British Pharmacological Society.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects

PubMed Central

Payne, Christopher D; Deeg, Mark A; Chan, Melanie; Tan, Lai Hock; LaBell, Elizabeth Smith; Shen, Tong; DeBrota, David J

2014-01-01

Aim The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. Methods This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. Results All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. Conclusion A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. PMID:25039273

Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV‐1106, a Long‐Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects

PubMed Central

Barkay, Hadas; Rasamoelisolo, Michele; Butler, Kathleen; Yamada, Kazumasa; Bassan, Merav; Yoon, Esther; Spiegelstein, Ofer

2016-01-01

Abstract TV‐1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long‐acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV‐1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV‐1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV‐1106 demonstrated relatively slow absorption (median tmax, 10–30 hours) and a mean elimination half‐life of 26–36 hours. Apparent clearance and volume of distribution decreased with increasing TV‐1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin‐like growth factor‐1 (IGF‐1) and IGF binding protein‐3 (IGFBP‐3) increased in a dose‐related manner, with maximum responses observed at 33–96 and 42–109 hours, respectively. IGF‐1 and IGFBP‐3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV‐1106, and 336 hours following 50 and 100 mg of TV‐1106. TV‐1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV‐1106 between Japanese and caucasian populations. The data also demonstrate long‐acting growth hormone properties of TV‐1106 and support its potential for once‐weekly dosing. PMID:27489211

Comparative pharmacokinetics/pharmacodynamics of clopidogrel besylate and clopidogrel bisulfate in healthy Korean subjects.

PubMed

Kim, Bo-Hyung; Kim, Jung-Ryul; Lim, Kyoung Soo; Shin, Hyun-Suk; Yoon, Seo Hyun; Cho, Joo-Youn; Jang, In-Jin; Shin, Sang-Goo; Yu, Kyung-Sang

2012-12-01

(clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the I(max) and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles. This study demonstrated that the pharmacokinetic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects.

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

PubMed Central

Moore, Kenneth Todd; Byra, William; Vaidyanathan, Seema; Natarajan, Jaya; Ariyawansa, Jay; Salih, Hiba; Turner, Kenneth C

2015-01-01

Aims The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. Methods An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. Results During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. Conclusions The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR. PMID:25475601

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

PubMed

Krishnaswami, Sriram; Boy, Mary; Chow, Vincent; Chan, Gary

2015-03-01

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. © 2014, The American College of Clinical Pharmacology.

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

PubMed Central

Louizos, Christopher; Yáñez, Jaime A.; Forrest, Laird; Davies, Neal M.

2015-01-01

Hysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed. PMID:24735761

Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects.

PubMed

Togawa, Michinori; Yamaya, Hidetoshi; Rodríguez, Mónica; Nagashima, Hirotaka

2016-12-01

Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). After single oral doses, maximum plasma concentrations (C max ) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: a Double-Blind Randomized Trial

PubMed Central

Chen, Beatrice A.; Panther, Lori; Marzinke, Mark A.; Hendrix, Craig W.; Hoesley, Craig J.; van der Straten, Ariane; Husnik, Marla J.; Soto-Torres, Lydia; Nel, Annalene; Johnson, Sherri; Richardson-Harman, Nicola; Rabe, Lorna K.; Dezzutti, Charlene S.

2015-01-01

Background Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. Methods MTN-013/IPM 026, a multi-site, double-blind, randomized, placebo-controlled trial in 48 HIV-negative U.S. women, evaluated vaginal rings containing dapivirine (25 mg) and maraviroc (100 mg), dapivirine-only, maraviroc-only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. Results There was no difference in related genitourinary adverse events between treatment arms compared to placebo. Dapivirine and maraviroc concentrations rose higher initially before falling more rapidly with the combination ring compared to relatively stable concentrations with the single drug rings. Dapivirine concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. Maraviroc was consistently detected only in CVF. Dapivirine and maraviroc CVF and dapivirine tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and dapivirine levels. Conclusions In this first study of a combination microbicide vaginal ring, all four rings were safe and well tolerated. Tissue dapivirine concentrations were 1,000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. Dapivirine, but not maraviroc, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Since maraviroc concentrations were consistently detectable only in CVF and not in plasma, improved drug release of maraviroc rings is needed. PMID:26034880

Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial.

PubMed

Chen, Beatrice A; Panther, Lori; Marzinke, Mark A; Hendrix, Craig W; Hoesley, Craig J; van der Straten, Ariane; Husnik, Marla J; Soto-Torres, Lydia; Nel, Annalene; Johnson, Sherri; Richardson-Harman, Nicola; Rabe, Lorna K; Dezzutti, Charlene S

2015-11-01

Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels. In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.

Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

PubMed Central

Gu, Ruo-lan; Liu, Liang; Xie, Liang-zhi; Gai, Wen-lin; Cao, Si-shuo; Meng, Zhi-yun; Gan, Hui; Wu, Zhuo-na; Li, Jian; Zheng, Ying; Zhu, Xiao-xia; Dou, Gui-fang

2016-01-01

Aim: SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. Methods: After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasma FVIII: C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1–200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss. Results: Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. Conclusion: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties. PMID:26806305

Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

PubMed

Lu, P; Fleischmann, R; Curtis, C; Ignatenko, S; Clarke, S H; Desai, M; Wong, S L; Grebe, K M; Black, K; Zeng, J; Stolzenbach, J; Medema, J K

2018-02-01

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

Pharmacokinetics and pharmacodynamics of vildagliptin in healthy Chinese volunteers.

PubMed

Hu, Pei; Yin, Qi; Deckert, Fabienne; Jiang, Ji; Liu, Dongyang; Kjems, Lise; Dole, William P; He, Yan-Ling

2009-01-01

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single-Ascending-Dose Study in Patients With Mild to Moderate Alzheimer Disease.

PubMed

Lu, Ming; Brashear, H Robert

2018-06-19

This study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending subcutaneous doses of bapineuzumab in patients with mild to moderate Alzheimer disease. Forty patients were randomized across 5 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 80 mg; 8 patients each [bapineuzumab 6; placebo 2]). The incidence of treatment-emergent adverse events (TEAEs) was higher in pooled bapineuzumab cohorts (83%) than in the pooled placebo group (27.7%). Most common TEAEs in the bapineuzumab group were gastrointestinal disorders and musculoskeletal and connective tissue disorders (bapineuzumab 17% each; placebo 0%). Serious TEAEs were observed in 7% of bapineuzumab-treated patients without any deaths or adverse event-related discontinuation. The median times to reach peak measurable concentration (C max ) of bapineuzumab were 14 days for 5-, 10-, and 20-mg cohorts, 11 days for 40-mg, and 7 days for 80-mg cohorts. The apparent volume of distribution of bapineuzumab was 134.29 to 204.68 mL/kg. The total body clearance was consistent at 10 to 80 mg. The average terminal half-life ranged from 26 to 46 days (5- to 80-mg groups). Exposure to bapineuzumab increased dose-proportionally from 10 to 80 mg. There was a positive correlation between C max and area under the concentration-time curve to the last measurable concentration (AUC last ) of plasma amyloid-β, and between the C max and AUC last of serum bapineuzumab. © 2018, The American College of Clinical Pharmacology.

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.

PubMed

de Haas, S L; Schoemaker, R C; van Gerven, J M A; Hoever, P; Cohen, A F; Dingemanse, J

2010-11-01

Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

PubMed

Chan, Noel; Sager, Philip T; Lawrence, Jack; Ortel, Thomas's; Reilly, Paul; Berkowitz, Scott; Kubitza, Dagmar; Eikelboom, John; Florian, Jeffry; Stockbridge, Norman; Rose, Martin; Temple, Robert; Seltzer, Jonathan H

2018-05-01

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. Copyright © 2017. Published by Elsevier Inc.

Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences.

PubMed

Romberg, Raymonda; Olofsen, Erik; Sarton, Elise; den Hartigh, Jan; Taschner, Peter E M; Dahan, Albert

2004-01-01

Morphine-6-glucuronide (M6G) is a metabolite of morphine and a micro-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design. Ten men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)-pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia. M6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 +/- 135 nm (population estimate +/- SE), the blood effect site equilibration half-life was 6.2 +/- 3.3 h, and the steepness parameter was 0.71 +/- 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency. A cumulative dose of 0.3 mg/kg M6G, given over 1 h, produces long-term analgesia greater than that observed with placebo, with equal dynamics (potency and speed of onset-offset) in men and women. Possible causes for the great intersubject response variability, such as genetic polymorphism of the

Comparative Safety and Tolerability of Anti-VEGF therapy in Age-Related Macular Degeneration

PubMed Central

Modi, Yasha S.; Tanchon, Carley; Ehlers, Justis P

2015-01-01

Neovascular age-related macular degeneration (NVAMD) is one of the leading causes of blindness. Over the last decade, the treatment of NVAMD has been revolutionized by the development intravitreal anti-vascular endothelial growth factor (VEGF) therapies. Several anti-VEGF medications are used for the treatment of NVAMD. The safety and tolerability of these medications deserve review given the high prevalence of NVAMD and the significant utilization of these medications. Numerous large randomized clinical trials have not shown any definitive differential safety relative to ocular or systemic safety of these medications. Intravitreal anti-VEGF therapy does appear to impact systemic VEGF levels, but the implications of these changes remain unclear. One unique safety concern relates drug compounding and the potential risks of contamination, specifically for bevacizumab. Continued surveillance for systemic safety concerns, particularly for rare events is merited. Overall these medications are well tolerated and effective in the treatment of NVAMD. PMID:25700714

Switching From Donepezil to Rivastigmine Is Well Tolerated: Results of an Open-Label Safety and Tolerability Study

PubMed Central

Sadowsky, Carl H.; Farlow, Martin R.; Atkinson, Leone; Steadman, Jennifer; Koumaras, Barbara; Chen, Michael; Mirski, Dario

2005-01-01

Background: Transitioning patients between cholinesterase inhibitors was thought to require a washout period to avoid cholinergic toxicity; however, evidence suggests that abrupt discontinuation of donepezil may lead to cognitive decline. We evaluated the safety and tolerability of an immediate switch from donepezil to rivastigmine. Method: This is an analysis of the safety and tolerability data from the first 28 days of an open-label, multicenter, prospective trial, conducted from August 2002 to August 2003, in which patients satisfying NINCDS-ADRDA criteria for probable Alzheimer's disease were administered rivastigmine 1.5 mg b.i.d. within 24 to 36 hours of donepezil discontinuation. Results are compared with adverse event rates from a retrospective analysis of a pivotal, placebo-controlled trial examining patients not previously treated with a cholinesterase inhibitor. Results: Fifty-eight of 61 patients completed the first 28 days, with no suspected drug-related discontinuations during this period. Incidence of overall gastrointestinal adverse events at day 7 was 8.2%, and at day 28 was 11.5%. The corresponding rate for rivastigmine-treated patients in the retrospective analysis of the pivotal trial for day 7 was 3.3%. Conclusion: These study results suggest that transitioning patients from donepezil to rivastigmine without a washout period is safe and well tolerated. PMID:15841194

Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example.

PubMed

Wiśniowska, Barbara; Polak, Sebastian

2016-11-01

A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher's human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded C max values below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro-in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK‐1 Inhibitor, After Short‐Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials

PubMed Central

Vanhoutte, Frédéric; Mazur, Minodora; Voloshyn, Oleksandr; Stanislavchuk, Mykola; Van der Aa, Annegret; Namour, Florence; Galien, René; Meuleners, Luc

2017-01-01

Objective JAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK‐1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors. Methods In two 4‐week exploratory, double‐blind, placebo‐controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS‐6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4. Results Treatment with filgotinib at 75–300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C‐reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30–300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK‐2 inhibition related], no effects on liver transaminases, and no increase in low‐density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK‐1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea. Conclusion Selective inhibition of JAK‐1 with filgotinib shows initial efficacy in

Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials.

PubMed

Vanhoutte, Frédéric; Mazur, Minodora; Voloshyn, Oleksandr; Stanislavchuk, Mykola; Van der Aa, Annegret; Namour, Florence; Galien, René; Meuleners, Luc; van 't Klooster, Gerben

2017-10-01

JAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK-1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors. In two 4-week exploratory, double-blind, placebo-controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS-6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4. Treatment with filgotinib at 75-300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C-reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30-300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK-2 inhibition related], no effects on liver transaminases, and no increase in low-density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK-1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea. Selective inhibition of JAK-1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory

Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules.

PubMed

Sankhala, Kamalesh; Takimoto, Chris H; Mita, Alain C; Xiong, Henry; Rodón, Jordi; Mehrvarz Sarshekeh, Amir; Burns, K; Iizuka, Kenzo; Kopetz, Scott

2018-04-18

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0-2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m 2 /day. At 3.0 mg/m 2 /day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m 2 /day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m 2 /day. The maximum tolerated dose was 3 mg/m 2 /day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m 2 /day and 3.0 mg/m 2 /day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

Development of description framework of pharmacodynamics ontology and its application to possible drug-drug interaction reasoning.

PubMed

Imai, Takeshi; Hayakawa, Masayo; Ohe, Kazuhiko

2013-01-01

Prediction of synergistic or antagonistic effects of drug-drug interaction (DDI) in vivo has been of considerable interest over the years. Formal representation of pharmacological knowledge such as ontology is indispensable for machine reasoning of possible DDIs. However, current pharmacology knowledge bases are not sufficient to provide formal representation of DDI information. With this background, this paper presents: (1) a description framework of pharmacodynamics ontology; and (2) a methodology to utilize pharmacodynamics ontology to detect different types of possible DDI pairs with supporting information such as underlying pharmacodynamics mechanisms. We also evaluated our methodology in the field of drugs related to noradrenaline signal transduction process and 11 different types of possible DDI pairs were detected. The main features of our methodology are the explanation capability of the reason for possible DDIs and the distinguishability of different types of DDIs. These features will not only be useful for providing supporting information to prescribers, but also for large-scale monitoring of drug safety.

Considerations on pharmacodynamics and pharmacokinetics: can everything be explained by the extent of drug binding to its receptor?

PubMed

Castañeda-Hernández, G; Granados-Soto, V

2000-03-01

It is frequently assumed that pharmacological responses depend solely on the extent of drug binding to its receptor according to the occupational theory. It is therefore presumed that the intensity of the effect is determined by drug concentration at its receptor site, yielding a unique concentration-effect relationship. However, when dependence, abstinence, and tolerance phenomena occur, as well as for pharmacological responses in vivo that are modulated by homeostatic mechanisms, the rate of drug input shifts the concentration-effect relationship. Hence, such responses cannot be explained on the sole basis of the extent of drug binding to its receptor. Information on the cellular and molecular processes involved in the generation of abstinence, dependence, and tolerance will undoubtedly result in the development of pharmacodynamic models allowing a satisfactory explanation of drug effects modulated by these phenomena. Notwithstanding, integrative physiology concepts are required to develop pharmacokinetic-pharmacodynamic models allowing the description of drug effects in an intact organism. It is therefore important to emphasize that integrative physiology cannot be neglected in pharmacology teaching and research, but should be considered as an equally valuable tool as molecular biology and other biomedical disciplines for the understanding of pharmacological effects.

Bioavailability, safety, and pharmacodynamics of delayed-release dexlansoprazole administered as two 30 mg orally disintegrating tablets or one 60 mg capsule.

PubMed

Kukulka, Michael; Nudurupati, Sai; Perez, Maria Claudia

2016-11-01

Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two dexlansoprazole 30 mg ODTs were compared with one dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study. Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5-10 days after the last dose of study drug. On day 1, peak observed plasma concentration ( C max ) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml). Systemic exposure, measured by the area under the plasma concentration-time curve (AUC), was approximately 25% lower after ODT administration. On day 5, mean pH after daily doses of two 30 mg ODT or one 60 mg capsule was 4.33 and 4.36, respectively; both regimens maintained intragastric pH above 4.0 for 60% of the 24-hour period. Headache was the most commonly reported adverse event (observed in 19.2% of participants); no adverse events leading to study withdrawal occurred. While systemic exposure (AUC) was 25% lower with ODT, peak concentrations ( C max ) after administration of two dexlansoprazole 30 mg ODTs and one 60 mg capsule were similar. The 24-hour intragastric pH control after administration of two dexlansoprazole 30 mg ODTs was equivalent to one dexlansoprazole 60 mg capsule. Both ODT and capsule were well tolerated.

Insulin glulisine: an evaluation of its pharmacodynamic properties and clinical application.

PubMed

Helms, Kristen L; Kelley, Kristi W

2009-04-01

To evaluate the pharmacodynamic properties, efficacy, safety, and clinical application of insulin glulisine, a rapid-acting insulin analog, in the treatment of diabetes mellitus in ambulatory and hospitalized patients. Searches were performed with the headings glulisine, insulin analog, [LysB3, GluB29] insulin, insulin glulisine, rDNA insulin, rapid-acting insulin, SoloStar, safety, efficacy, pharmacodynamics, and cost analysis within MEDLINE and PubMed, American Diabetes Association (ADA), the Food and Drug Administration (FDA), and Sanofi-aventis Pharmaceuticals (1990-August 2008). Phase 1, Phase 2, Phase 3, and postmarketing trials examining the efficacy and safety of glulisine in type 1 or type 2 diabetes were reviewed. Studies published as abstracts and the manufacturer's product information supplemented data absent from clinical trials. Insulin glulisine is a rapid-acting insulin with relative equivalence in efficacy and safety to other short- and rapid-acting insulins. Glulisine's onset of action of 20 minutes and 4-hour duration of action allow for bolus administration 15-20 minutes prior to or up to 20 minutes after meals. Clinical trials have demonstrated the safety and efficacy in adults with type 1 or type 2 diabetes. Several studies indicated a statistically significant decrease of hemoglobin A1C (A1C) with glulisine compared with regular insulin (0.10 decrease); however, no difference in A1C control was found compared with insulin aspart or lispro. Significant adverse effects appear to be limited to localized and systemic allergic reactions and hypoglycemia. Insulin glulisine is a safe and effective rapid-acting insulin analog for the treatment of adults with diabetes. Clinical benefit over other short- and rapid-acting insulin products is not established. Addition of insulin glulisine to a formulary should be based on institution-specific availability and cost differences between glulisine, lispro, and aspart in the absence of superiority of clinical

Systematic review of safety and tolerability of a complex micronutrient formula used in mental health.

PubMed

Simpson, J Steven A; Crawford, Susan G; Goldstein, Estelle T; Field, Catherine; Burgess, Ellen; Kaplan, Bonnie J

2011-04-18

Theoretically, consumption of complex, multinutrient formulations of vitamins and minerals should be safe, as most preparations contain primarily the nutrients that have been in the human diet for millennia, and at safe levels as defined by the Dietary Reference Intakes. However, the safety profile of commercial formulae may differ from foods because of the amounts and combinations of nutrients they contain. As these complex formulae are being studied and used clinically with increasing frequency, there is a need for direct evaluation of safety and tolerability. All known safety and tolerability data collected on one complex nutrient formula was compiled and evaluated. Data were assembled from all the known published and unpublished studies for the complex formula with the largest amount of published research in mental health. Biological safety data from 144 children and adults were available from six sources: there were no occurrences of clinically meaningful negative outcomes/effects or abnormal blood tests that could be attributed to toxicity. Adverse event (AE) information from 157 children and adults was available from six studies employing the current version of this formula, and only minor, transitory reports of headache and nausea emerged. Only one of the studies permitted a direct comparison between micronutrient treatment and medication: none of the 88 pediatric and adult participants had any clinically meaningful abnormal laboratory values, but tolerability data in the group treated with micronutrients revealed significantly fewer AEs and less weight gain. This compilation of safety and tolerability data is reassuring with respect to the broad spectrum approach that employs complex nutrient formulae as a primary treatment.

Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination.

PubMed

Hysek, Cédric M; Simmler, Linda D; Schillinger, Nathalie; Meyer, Nicole; Schmid, Yasmin; Donzelli, Massimiliano; Grouzmann, Eric; Liechti, Matthias E

2014-03-01

Methylphenidate and 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') are widely misused psychoactive drugs. Methylphenidate increases brain dopamine and norepinephrine levels by blocking the presynaptic reuptake transporters. MDMA releases serotonin, dopamine and norepinephrine through the same transporters. Pharmacodynamic interactions of methylphenidate and MDMA are likely. This study compared the pharmacodynamic and pharmacokinetic effects of methylphenidate and MDMA administered alone or in combination in healthy subjects using a double-blind, placebo-controlled, crossover design. Methylphenidate did not enhance the psychotropic effects of MDMA, although it produced psychostimulant effects on its own. The haemodynamic and adverse effects of co-administration of methylphenidate and MDMA were significantly higher compared with MDMA or methylphenidate alone. Methylphenidate did not change the pharmacokinetics of MDMA and vice versa. Methylphenidate and MDMA shared some subjective amphetamine-type effects; however, 125 mg of MDMA increased positive mood more than 60 mg of methylphenidate, and methylphenidate enhanced activity and concentration more than MDMA. Methylphenidate and MDMA differentially altered facial emotion recognition. Methylphenidate enhanced the recognition of sad and fearful faces, whereas MDMA reduced the recognition of negative emotions. Additionally, the present study found acute pharmacodynamic tolerance to MDMA but not methylphenidate. In conclusion, the combined use of methylphenidate and MDMA does not produce more psychoactive effects compared with either drug alone, but potentially enhances cardiovascular and adverse effects. The findings may be of clinical importance for assessing the risks of combined psychostimulant misuse. Trial registration identification number: NCT01465685 (http://clinicaltrials.gov/ct2/show/NCT01465685).

A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects.

PubMed

Park, Sang-In; Lee, Howard; Oh, Jaeseong; Lim, Kyoung Soo; Jang, In-Jin; Kim, Jeong-Ae; Jung, Jong Hyuk; Yu, Kyung-Sang

2015-01-01

In type 2 diabetes mellitus, fixed-dose combination (FDC) can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD), pharmacokinetic (PK), and tolerability profiles of gemigliptin and extended-release metformin (metformin XR) between FDC and separate tablets. A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1) and metformin XR (500 mg ×2) were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4) activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs) of FDC to separate tablet formulations and their 90% confidence intervals (CIs) were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study. The plasma DPP-4 activity-time curves of the FDC and the separate tablets almost overlapped, leading to a GMR (90% CI) of the FDC to separate tablets for the plasma DPP-4 activity and its maximum inhibition of 1.00 (0.97-1.04) and 0.92 (0.82-1.05), respectively. Likewise, all of the GMRs (90% CIs) of FDC to separate tablets for the area under the plasma concentration-time curve and maximum plasma concentration of gemigliptin and metformin fell entirely within the conventional bioequivalence range of 0.80-1.25. Both the FDC and separate tablets were well tolerated. The PD, PK, and tolerability profiles of gemigliptin and metformin XR in FDC and separate tablets were found to be comparable. The FDC tablet of gemigliptin and metformin

Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

PubMed

Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

2013-11-01

Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women

PubMed Central

Franconi, Flavia; Campesi, Ilaria

2014-01-01

Pharmacological response depends on multiple factors and one of them is sex–gender. Data on the specific effects of sex–gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex–gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex–gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex–gender-based approach with the aim of tailoring therapies to an individual's needs and concerns. Linked Articles This article is part of a themed section on Biological Sex and Cardiovascular Pharmacology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-3 PMID:23981051

Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability.

PubMed

Johnson, Franklin; Setnik, Beatrice

2011-01-01

Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients. Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MS-sNT is taken as directed. The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS). Naltrexone from MS-sNTC met criteria for equivalent

Safety and Tolerability of Methylphenidate in Preschool Children with ADHD

ERIC Educational Resources Information Center

Wigal, Tim; Greenhill, Laurence; Chuang, Shirley; McGough, James; Vitiello, Benedetto; Skrobala, Anne; Swanson, James; Wigal, Sharon; Abikoff, Howard; Kollins, Scott; McCracken, James; Riddle, Mark; Posner, Kelly; Ghuman, Jaswinder; Davies, Mark; Thorp, Ben; Stehli, Annamarie

2006-01-01

Objective: To report on the safety and tolerability of methylphenidate (MPH) 3- to 5-year-old children with attention-deficit/hyperactivity disorder (ADHD) during 1 year of treatment. Method: Exactly 183 children (3-5 years old) entered a treatment study of MPH, consisting of a 1-week open-label lead-in (n = 183); a 5-week placebo-controlled,…

A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers.

PubMed

Kostic, Ana; King, Thomas Alexander; Yang, Feng; Chan, Kuo-Chen; Yancopoulos, George D; Gromada, Jesper; Harp, Joyce B

2018-02-01

Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double-blinded trial. Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose-lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges. REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC 0-90 minutes ) by 80% to 90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups. REGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

PubMed Central

Kostic, Ana; King, Thomas Alexander; Yang, Feng; Chan, Kuo‐Chen; Yancopoulos, George D.; Gromada, Jesper

2017-01-01

Aims Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first‐in‐human healthy volunteer randomized double‐blinded trial. Methods Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose‐lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges. Results REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose‐dependent increases in hepatic aminotransferases. No increase in LDL‐C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration‐time profiles suggest a 2‐compartment disposition and marked nonlinearity, consistent with target‐mediated clearance. REGN1193 inhibited the glucagon‐stimulated glucose increase in a dose‐dependent manner. The 0.6 mg/kg dose inhibited the glucagon‐induced glucose area under the curve for 0 to 90 minutes (AUC0‐90 minutes) by 80% to 90% on days 3 and 15, while blunting the increase in C‐peptide. REGN1193 dose‐dependently increased total GLP‐1, GLP‐2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups. Conclusion REGN1193, a GCGR‐blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here

A study of potential pharmacokinetic and pharmacodynamic interactions between dextromethorphan/quinidine and memantine in healthy volunteers.

PubMed

Pope, Laura E; Schoedel, Kerri A; Bartlett, Cynthia; Sellers, Edward M

2012-08-01

Dextromethorphan/quinidine (DMQ) is the first agent indicated for the treatment of pseudobulbar affect. Dextromethorphan, the active ingredient, is a low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. This study evaluated the potential for a drug-drug interaction (DDI) of DMQ with memantine, which is also an NMDA receptor antagonist. This open-label, randomized, parallel-group study enrolled healthy adults who were randomized into one of two treatment groups. Group 1 subjects were administered memantine at a starting dose of 5 mg once daily, which was titrated over a 3-week period to a dose of 10 mg twice daily (every 12 hours) and continued for another 11 days to attain steady state; DMQ 30 mg (dextromethorphan 30 mg/quinidine 30 mg) every 12 hours was then added for a further 8 days. Group 2 subjects received DMQ 30 mg every 12 hours for 8 days to attain steady state; memantine was then added, titrated on the same schedule as in group 1, and continued at 10 mg every 12 hours for an additional 11 days. Pharmacokinetic blood sampling was performed to assess the primary endpoints of the 90% confidence intervals (CIs) for the geometric mean ratios of the areas under the plasma concentration-time curves (AUCs) for memantine, dextromethorphan, dextrorphan - the dextromethorphan metabolite - and quinidine during concomitant therapy versus monotherapy. Safety/tolerability and pharmacodynamic variables were also assessed. A total of 52 subjects were randomized. In both group 1 (n = 23) and group 2 (n = 29), the 90% CIs for the ratios of the AUCs during concomitant therapy versus monotherapy were within the predefined range to indicate similarity (0.8-1.25) for memantine, dextromethorphan and dextrorphan, indicating no pharmacokinetic DDI. The 90% CI for the AUC ratio for quinidine was slightly above the predefined range; however, the mean AUC increased by only 25%. In both groups, incidence of adverse events was similar, and pharmacodynamic

Safety and tolerability of new-generation anti-obesity medications: a narrative review.

PubMed

Patel, Dhiren K; Stanford, Fatima Cody

2018-03-01

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk-benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk-benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk-benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk-benefit.

Systematic review of safety and tolerability of a complex micronutrient formula used in mental health

PubMed Central

2011-01-01

Background Theoretically, consumption of complex, multinutrient formulations of vitamins and minerals should be safe, as most preparations contain primarily the nutrients that have been in the human diet for millennia, and at safe levels as defined by the Dietary Reference Intakes. However, the safety profile of commercial formulae may differ from foods because of the amounts and combinations of nutrients they contain. As these complex formulae are being studied and used clinically with increasing frequency, there is a need for direct evaluation of safety and tolerability. Methods All known safety and tolerability data collected on one complex nutrient formula was compiled and evaluated. Results Data were assembled from all the known published and unpublished studies for the complex formula with the largest amount of published research in mental health. Biological safety data from 144 children and adults were available from six sources: there were no occurrences of clinically meaningful negative outcomes/effects or abnormal blood tests that could be attributed to toxicity. Adverse event (AE) information from 157 children and adults was available from six studies employing the current version of this formula, and only minor, transitory reports of headache and nausea emerged. Only one of the studies permitted a direct comparison between micronutrient treatment and medication: none of the 88 pediatric and adult participants had any clinically meaningful abnormal laboratory values, but tolerability data in the group treated with micronutrients revealed significantly fewer AEs and less weight gain. Conclusions This compilation of safety and tolerability data is reassuring with respect to the broad spectrum approach that employs complex nutrient formulae as a primary treatment. PMID:21501484

Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review.

PubMed

Cañas, Fernando; Möller, Hans-Jürgen

2010-09-01

Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP). Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency. RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI. Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.

Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers.

PubMed

Cho, Doo-Yeoun; Bae, Soo Hyeon; Lee, Joeng Kee; Park, Jung Bae; Kim, Yang-Weon; Lee, Sukhyang; Oh, Euichaul; Kim, Bom-Taeck; Bae, Soo Kyung

2015-03-01

1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects. 2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. 3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUCt of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17-2.31) and by 51% (1.51; 1.17-2.31), respectively. Similar patterns were observed for the increase in Cmax of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. 4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.

An Integrated Fault Tolerant Robotic Controller System for High Reliability and Safety

NASA Technical Reports Server (NTRS)

Marzwell, Neville I.; Tso, Kam S.; Hecht, Myron

1994-01-01

This paper describes the concepts and features of a fault-tolerant intelligent robotic control system being developed for applications that require high dependability (reliability, availability, and safety). The system consists of two major elements: a fault-tolerant controller and an operator workstation. The fault-tolerant controller uses a strategy which allows for detection and recovery of hardware, operating system, and application software failures.The fault-tolerant controller can be used by itself in a wide variety of applications in industry, process control, and communications. The controller in combination with the operator workstation can be applied to robotic applications such as spaceborne extravehicular activities, hazardous materials handling, inspection and maintenance of high value items (e.g., space vehicles, reactor internals, or aircraft), medicine, and other tasks where a robot system failure poses a significant risk to life or property.

SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF THE COMBINATION OF SORAFENIB AND TANESPIMYCIN

PubMed Central

Vaishampayan, Ulka N.; Burger, Angelika M.; Sausville, Edward A.; Heilbrun, Lance K.; Li, Jing; Horiba, Naomi; Egorin, Merrill J.; Ivy, Percy; Pacey, Simon; Lorusso, Patricia M.

2010-01-01

PURPOSE Heat shock protein 90 inhibition affects the Raf-kinase signaling pathway and could enhance anti-tumor effects of sorafenib, a Raf-kinase inhibitor. The combination of sorafenib and tanespimycin (17-AAG/17-allyl-amino-geldanamycin; NSC # 330507/KOS-953) was evaluated in a phase I trial with the primary objective of defining a phase II dose PATIENTS AND METHODS The dose cohorts consisted of fixed continuous oral dosing of sorafenib 400 mg twice daily, starting 14 days prior to tanespimycin which was administered intravenously, at escalating doses, (starting at 300 mg/m,2 with 50 mg/m2 increments), on days 1, 8 and 15, in a 28-day cycle. Toxicity was assessed weekly; response was evaluated every 2 cycles. RESULTS Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were: renal cancer (12), melanoma (6) and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in 1 patient each were observed at 450 mg/m2 of tanespimycin. 114 cycles were administered with a median of four cycles (range 1–17 cycles). Plasma concentrations of sorafenib and metabolites reached steady-state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients CONCLUSIONS Recommended phase II doses of this combination are sorafenib 400 mg twice daily and tanespimycin 400 mg/m2 on days 1, 8 and 15 every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma. PMID:20525756

Population Pharmacokinetics and Exposure-Response (Efficacy and Safety/Tolerability) of Empagliflozin in Patients with Type 2 Diabetes.

PubMed

Baron, Kyle T; Macha, Sreeraj; Broedl, Uli C; Nock, Valerie; Retlich, Silke; Riggs, Matthew

2016-09-01

The aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure-response (E-R) for efficacy (fasting plasma glucose, glycated hemoglobin) and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus. This study extends the findings of previous analyses which described the PK and pharmacodynamics (PD) using early clinical studies of up to 12 weeks in duration. Population pharmacokinetic and E-R models were developed based on two Phase I, four Phase II, and four Phase III studies. Variability in empagliflozin exposure was primarily affected by estimated glomerular filtration rate (eGFR) (less than twofold increase in exposure in patients with severe renal impairment). Consistent with its mode of action, the efficacy of empagliflozin was increased with elevated baseline plasma glucose levels and attenuated with decreasing renal function, but was still maintained to nearly half the maximal effect with eGFR as low as 30 mL/min/1.73 m(2). All other investigated covariates, including sex, body mass index, race, and age did not alter the PK or efficacy of empagliflozin to a clinically relevant extent. Compared with placebo, empagliflozin administration was associated with an exposure-independent increase in the incidence of genital infections and no significant change in the risk of UTI, hypoglycemia, or volume depletion. Based on the results from the PK and E-R analysis, no dose adjustment is required for empagliflozin in the patient population for which the drug is approved. Boehringer Ingelheim.

29 CFR 5.15 - Limitations, variations, tolerances, and exemptions under the Contract Work Hours and Safety...

Code of Federal Regulations, 2010 CFR

2010-07-01

... the Contract Work Hours and Safety Standards Act. 5.15 Section 5.15 Labor Office of the Secretary of... WORK HOURS AND SAFETY STANDARDS ACT) Davis-Bacon and Related Acts Provisions and Procedures § 5.15 Limitations, variations, tolerances, and exemptions under the Contract Work Hours and Safety Standards Act. (a...

Safety and tolerability of transcranial direct current stimulation to stroke patients - A phase I current escalation study.

PubMed

Chhatbar, Pratik Y; Chen, Rong; Deardorff, Rachael; Dellenbach, Blair; Kautz, Steven A; George, Mark S; Feng, Wuwei

A prior meta-analysis revealed that higher doses of transcranial direct current stimulation (tDCS) have a better post-stroke upper-extremity motor recovery. While this finding suggests that currents greater than the typically used 2 mA may be more efficacious, the safety and tolerability of higher currents have not been assessed in stroke patients. We aim to assess the safety and tolerability of single session of up to 4 mA in stroke patients. We adapted a traditional 3 + 3 study design with a current escalation schedule of 1»2»2.5»3»3.5»4 mA for this tDCS safety study. We administered one 30-min session of bihemispheric montage tDCS and simultaneous customary occupational therapy to patients with first-ever ischemic stroke. We assessed safety with pre-defined stopping rules and investigated tolerability through a questionnaire. Additionally, we monitored body resistance and skin temperature in real-time at the electrode contact site. Eighteen patients completed the study. The current was escalated to 4 mA without meeting the pre-defined stopping rules or causing any major safety concern. 50% of patients experienced transient skin redness without injury. No rise in temperature (range 26°C-35 °C) was noted and skin barrier function remained intact (i.e. body resistance >1 kΩ). Our phase I safety study supports that single session of bihemispheric tDCS with current up to 4 mA is safe and tolerable in stroke patients. A phase II study to further test the safety and preliminary efficacy with multi-session tDCS at 4 mA (as compared with lower current and sham stimulation) is a logical next step. ClinicalTrials.gov Identifier: NCT02763826. Copyright © 2017 Elsevier Inc. All rights reserved.

Fall Protection Characteristics of Safety Belts and Human Impact Tolerance.

PubMed

Hino, Yasumichi; Ohdo, Katsutoshi; Takahashi, Hiroki

2014-08-23

Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt 1) , which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness 2, 3) , which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference 4-9) to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model 10) was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls.

Fall protection characteristics of safety belts and human impact tolerance.

PubMed

Hino, Yasumichi; Ohdo, Katsutoshi; Takahashi, Hiroki

2014-01-01

Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt, which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness, which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls.

Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies

PubMed Central

Schweizer, Anja; Dejager, Sylvie; Foley, James E; Kothny, Wolfgang

2011-01-01

Aim: Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including incidences of the most common adverse events (AEs), of vildagliptin based on a large pooled database of Phase II and III clinical trials. Methods: Safety data were pooled from 38 studies of ≥12 to ≥104 weeks’ duration. AE profiles of vildagliptin (50 mg bid; N = 6116) were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210). Absolute incidence rates were calculated for all AEs, serious AEs (SAEs), discontinuations due to AEs, and deaths. Results: Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively) and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively), whereas drug-related AEs were seen with a lower frequency in vildagliptin-treated patients (15.7% vs 21.7% with comparators). The incidences of the most commonly reported specific AEs were also similar between vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas. Conclusions: The present pooled analysis shows that vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies. PMID:21415917

Pharmacokinetics and Pharmacodynamics in Space

NASA Technical Reports Server (NTRS)

Putcha, Lakshmi; Cintron, Nitza M.

1990-01-01

The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic

Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties

PubMed Central

Hay, Justin L.; Sitsen, Elske; Dahan, Albert; Klaassen, Erica; Houghton, William; Groeneveld, Geert Jan

2016-01-01

Aim Xen2174 is a synthetic 13‐amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects. Methods This was a randomized, blinded, placebo‐controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks). Results Twenty‐five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration–time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post‐lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg–placebo (95% confidence interval), 22.2% (−5.0%, 57.1%); P = 0.1131]. Conclusions At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed. PMID:27987228

Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033

PubMed Central

Tran, Jonathan Q.; Rana, Jitesh; Barkhof, Frederik; Melamed, Isaac; Gevorkyan, Hakop; Wattjes, Mike P.; de Jong, Remko; Brosofsky, Kristin; Ray, Soma; Xu, Lei; Zhao, Jim; Parr, Edward

2014-01-01

Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS). Methods: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1–100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3–100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated. Results: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low. Conclusions: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders. Classification of evidence: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0–7.6%). PMID:25340070

Fall Protection Characteristics of Safety Belts and Human Impact Tolerance

PubMed Central

HINO, Yasumichi; OHDO, Katsutoshi; TAKAHASHI, Hiroki

2014-01-01

Abstract: Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt1), which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness2, 3), which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference4,5,6,7,8,9) to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model10) was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls. PMID:25345426

Hypothermia for preventing chemotherapy-induced neuropathy - a pilot study on safety and tolerability in healthy controls.

PubMed

Bandla, Aishwarya; Sundar, Raghav; Liao, Lun-De; Sze Hui Tan, Stacey; Lee, Soo-Chin; Thakor, Nitish V; Wilder-Smith, Einar P V

2016-01-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of several chemotherapeutic agents, often leading to treatment discontinuation. Up to 20% of patients treated with weekly paclitaxel experience severe CIPN and no effective treatment has been established so far. The mechanisms of CIPN damage are unclear, but are directly dose-related. We had earlier demonstrated, in rats, the influence of hypothermia in reducing nerve blood flow. Here, we hypothesize that continuous flow limb hypothermia during chemotherapy reduces the incidence and severity of CIPN, by limiting deliverance of the neurotoxic drug to the peripheral nerves. In this study, prior to assessing the effect of hypothermia in preventing CIPN in cancer subjects undergoing paclitaxel chemotherapy, we assess the safety and tolerable temperatures for limb hypothermia in healthy human subjects. In 15 healthy human subjects, hypothermia was administered as continuous flow cooling, unilaterally, via a thermoregulator setup covering the digits up to the elbow/knee, along with continuous skin temperature monitoring. Thermoregulator coolant temperatures between 25 °C and 20 °C were tested for tolerability, based on a carefully designed temperature regulation protocol, and maintained for three hours mimicking the duration of chemotherapy. Tolerability was evaluated using various safety and tolerability scores to monitor the subjects. At the end of the cooling session the healthy subjects presented without significant adverse effects, the main being brief mild skin erythema and transient numbness. Coolant temperatures as low as 22 °C were well tolerated continuously over three hours. Our results confirm the safety and tolerability of continuous flow limb hypothermia in healthy subjects. Further studies will use 22 °C thermoregulator temperature to investigate hypothermia in preventing CIPN in breast cancer patients receiving adjuvant weekly paclitaxel. This pilot study

Clinical Pharmacodynamics: Principles of Drug Response and Alterations in Kidney Disease.

PubMed

Keller, Frieder; Hann, Alexander

2018-05-16

Pharmacokinetics and pharmacodynamics follow the logic of cause and consequence. Receptor-mediated and reversible effects can be distinguished from direct and irreversible effects. Reversible effects are capacity-limited and saturable whereas irreversible effects are limited only by the number of viable targets. In the case of receptor-mediated and reversible effects a threshold and a ceiling concentration can be defined. Antimicrobial drugs with concentration-dependent action are distinguished from drugs with time-dependent action. Concentration-dependent effects are associated with a high ceiling concentration and the target is the high peak. Time-dependent effects are associated with a high threshold concentration and the target is the high trough. During kidney dysfunction, alterations of drug response are usually attributed to pharmacokinetic but rarely to pharmacodynamic changes. Dose adjustment calculations, therefore, tacitly presume that pharmacodynamic parameters remain unchanged while only pharmacokinetic parameters are altered in kidney failure. Kidney dysfunction influences the pharmacokinetic parameters of at least 50% of all essential drugs. Clinicians usually consider pharmacokinetics when kidney disease is found, but pharmacodynamics is as important. Alterations of pharmacodynamic parameters are conceivable but only rarely reported in kidney failure. Sometimes surprising dosing adjustments are needed when pharmacodynamic concepts are brought into the decision process of which dose to choose. Pharmacokinetics and pharmacodynamics should both be considered when any dosing regimen is determined. Copyright © 2018 by the American Society of Nephrology.

Workplace Violence and Perceptions of Safety Among Emergency Department Staff Members: Experiences, Expectations, Tolerance, Reporting, and Recommendations.

PubMed

Copeland, Darcy; Henry, Melissa

Workplace violence (WPV) is a widely recognized problem in emergency departments (EDs). The majority of WPV studies do not include nonclinical staff and do not address expectations of violence, tolerance to violence, or perceptions of safety. Among a multidisciplinary sample of ED staff members, specific study aims were to (a) describe exposure to WPV; (b) describe perceptions of safety, tolerance to violence, and expectation of violence; (c) describe reporting behaviors and perceived barriers to reporting violence; (d) examine relationships between demographic variables, experiences of violence, tolerance to violence, perceptions of safety, and reporting behaviors; and (e) identify perceptions of viable interventions to improve workplace safety. A cross-sectional design was used to survey ED staff members in a Level 1 Shock Trauma center. Eleven disciplines were represented in 147 completed surveys; 88% of respondents reported exposure to WPV in the previous 6 months. Members of every discipline reported exposure to WPV; 98% of the sample felt safe at work and 64% felt violence was an expected part of the job. Most violence was not reported, primarily because "nobody was hurt." Emergency department staff members expected and experienced violence; nevertheless, there was a widespread perception of safety. Perceptions of safety and reasons for not reporting did not mirror previous findings. The WPV exposure is not isolated to clinical staff members and occurs even when prevention strategies are in place. The definition of WPV and the individual's interpretation of the event might preclude reporting.

Pilot Study on the Safety and Tolerability of Extended Release Niacin for HIV-infected Patients with Hypertriglyceridemia

PubMed Central

Souza, Scott A; Walsh, Erica J; Shippey, Ford; Shikuma, Cecilia

2010-01-01

Background To determine the safety and tolerability of extended release niacin (ERN) in HIV-infected patients. Methods This was a pilot, open-label, 36 week study evaluating the safety and tolerability of ERN in HIV-infected patients with hypertriglyceridemia. Subjects with cardiovascular disease, diabetes or liver disease were excluded. Subjects with persistent elevation of triglyceride (TG) >200 after 8 weeks on American Heart Association Step One and Two Diets were started on ERN 500mg once daily, with continuation of the diet and exercise recommendations until the end of the study. ERN was increased by 500mg every 4 weeks, to a maximum of 1500mg/day, depending on subject tolerability. Safety and tolerability of ERN were assessed. Results Ten subjects enrolled received ERN. Dose titration and maintenance to 1500mg/day were achieved in all 10 subjects. No subject required dose adjustment. Mild flushing was experienced in 8 subjects. Asymptomatic hypophosphotemia was noted in 4 subjects; all resolved with oral phosphate supplementation. Median TG was reduced by 254 mg/dL (p<0.05). Non-significant changes were noted in liver enzymes, HDL, LDL, and total cholesterol. Fasting insulin and glucose levels did not change with treatment. Conclusion In this pilot study, ERN was well-tolerated and resulted in reduction of TG. Although the results of this study are promising, the study is limited in the small number of subjects. Further investigation is warranted. PMID:20533755

Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of monoclonal antibodies in children.

PubMed

Edlund, Helena; Melin, Johanna; Parra-Guillen, Zinnia P; Kloft, Charlotte

2015-01-01

Monoclonal antibodies (mAbs) constitute a therapeutically and economically important drug class with increasing use in both adult and paediatric patients. The rather complex pharmacokinetic and pharmacodynamic properties of mAbs have been extensively reviewed in adults. In children, however, limited information is currently available. This paper aims to comprehensively review published pharmacokinetic and pharmacokinetic-pharmacodynamic studies of mAbs in children. The current status of mAbs in the USA and in Europe is outlined, including a critical discussion of the dosing strategies of approved mAbs. The pharmacokinetic properties of mAbs in children are exhaustively summarised along with comparisons to reports in adults: for each pharmacokinetic process, we discuss the general principles and mechanisms of the pharmacokinetic/pharmacodynamic characteristics of mAbs, as well as key growth and maturational processes in children that might impact these characteristics. Throughout this review, considerable knowledge gaps are identified, especially regarding children-specific properties that influence pharmacokinetics, pharmacodynamics and immunogenicity. Furthermore, the large heterogeneity in the presentation of pharmacokinetic/pharmacodynamic data limited clinical inferences in many aspects of paediatric mAb therapy. Overall, further studies are needed to fully understand the impact of body size and maturational changes on drug exposure and response. To maximise future knowledge gain, we propose a 'Guideline for Best Practice' on how to report pharmacokinetic and pharmacokinetic-pharmacodynamic results from mAb studies in children which also facilitates comparisons. Finally, we advocate the use of more sophisticated modelling strategies (population analysis, physiology-based approaches) to appropriately characterise pharmacokinetic-pharmacodynamic relationships of mAbs and, thus, allow for a more rational use of mAb in the paediatric population.

Safety envelope for load tolerance of structural element design based on multi-stage testing

DOE PAGES

Park, Chanyoung; Kim, Nam H.

2016-09-06

Structural elements, such as stiffened panels and lap joints, are basic components of aircraft structures. For aircraft structural design, designers select predesigned elements satisfying the design load requirement based on their load-carrying capabilities. Therefore, estimation of safety envelope of structural elements for load tolerances would be a good investment for design purpose. In this article, a method of estimating safety envelope is presented using probabilistic classification, which can estimate a specific level of failure probability under both aleatory and epistemic uncertainties. An important contribution of this article is that the calculation uncertainty is reflected in building a safety envelope usingmore » Gaussian process, and the effect of element test data on reducing the calculation uncertainty is incorporated by updating the Gaussian process model with the element test data. It is shown that even one element test can significantly reduce the calculation uncertainty due to lacking knowledge of actual physics, so that conservativeness in a safety envelope is significantly reduced. The proposed approach was demonstrated with a cantilever beam example, which represents a structural element. The example shows that calculation uncertainty provides about 93% conservativeness against the uncertainty due to a few element tests. As a result, it is shown that even a single element test can increase the load tolerance modeled with the safety envelope by 20%.« less

Efficacy, safety, tolerability and price of newly approved drugs in solid tumors.

PubMed

Barnes, Tristan A; Amir, Eitan; Templeton, Arnoud J; Gomez-Garcia, Susana; Navarro, Beatriz; Seruga, Bostjan; Ocana, Alberto

2017-05-01

New anti-cancer drugs utilize diverse mechanisms of action. Here we evaluate their differential efficacy, safety, tolerability and price. Drugs approved for solid tumor treatment between 2000 and 2015 were identified and analyzed in subgroups: agents targeting oncogenes (group 1), anti-angiogenics (group 2), immunotherapy (group 3), and chemotherapy (group 4). Hazard ratios (HRs) were extracted from the registration trials and pooled in a meta-analysis. Odds ratios for toxic death, treatment discontinuation and grade 3-4 toxicity were compared to control groups. The Micromedex Red Book was used to calculate the monthly price. Analysis included 74 studies comprising 48,527 patients. Progression-free survival (PFS) was improved to a greater degree with groups 1 and 2 than with groups 3 and 4, (pooled HR: 0.54, 0.56, 0.63, and 0.76 for groups 1-4 respectively, p for difference <0.001). Compared to PFS, there was a lower magnitude of improvement overall survival in all groups and the degree of benefit was less for group 4 than for other groups (pooled HR: 0.77, 0.78, 0.68, and 0.83 for groups 1-4 respectively, p for difference=0.007). Compared to control groups in individual trials, immunotherapy was associated with better safety and tolerability than other groups. Drug prices have increased over time with no significant difference between groups. There was no meaningful correlation between pricing and efficacy. Compared to control groups, immunotherapeutics and drugs targeting oncogenes or angiogenesis improve efficacy to a greater degree than chemotherapy. Immunotherapy appears to have better safety and tolerability profile compared to other cancer therapies. Market price of drugs is not related to efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria.

PubMed

Varo, Rosauro; Crowley, Valerie M; Sitoe, Antonio; Madrid, Lola; Serghides, Lena; Bila, Rubao; Mucavele, Helio; Mayor, Alfredo; Bassat, Quique; Kain, Kevin C

2017-05-23

Despite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high. Adjunctive therapies that target the host response to malaria infection may further decrease mortality over that of anti-malarial agents alone. Peroxisome proliferator-activated receptor-gamma agonists (e.g. rosiglitazone) have been shown to act on several pathways implicated in the pathogenesis of severe malaria and may improve clinical outcome as an adjunctive intervention. In this study, the safety and tolerability of adjunctive rosiglitazone in paediatric uncomplicated malaria infection was evaluated in Mozambique, as a prelude to its evaluation in a randomized controlled trial in paediatric severe malaria. The study was a prospective, randomized, double-blind, placebo-controlled, phase IIa trial of rosiglitazone (0.045 mg/kg/dose) twice daily for 4 days versus placebo as adjunctive treatment in addition to Mozambican standard of care (artemisinin combination therapy Coartem ® ) in children with uncomplicated malaria. The primary outcomes were tolerability and safety, including clinical, haematological, biochemical, and electrocardiographic evaluations. Thirty children were enrolled: 20 were assigned to rosiglitazone and 10 to placebo. Rosiglitazone treatment did not induce hypoglycaemia nor significantly alter clinical, biochemical, haematological, or electrocardiographic parameters. Adjunctive rosiglitazone was safe and well-tolerated in children with uncomplicated malaria, permitting the extension of its evaluation as adjunctive therapy for severe malaria. The trial is registered with Clinicaltrials.gov, NCT02694874.

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects.

PubMed

Krishna, Rajesh; Gheyas, Ferdous; Liu, Yang; Cote, Josee; Laterza, Omar; Ruckle, Jon L; Wagner, John A; Denker, Andrew E

2018-02-01

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects. © 2017, The American College of Clinical Pharmacology.

Pharmacokinetics and Pharmacodynamics of Oximes in Unanesthetized Pigs

DTIC Science & Technology

1991-04-01

D-A234 036 U.S. ARMY MEDICAL RESEARCH p INSTITUTE OF CHEMICAL DEFENSE USAMRICD-TR-91-07 PHARMACOKINETICS AND PHARMACODYNAMICS OF OXIMES IN...SUBJECT TERMS (Continue on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP 2-PAM Cl, ICD 467, MMB-4, Pharmacokinetics ...Cardiovascular 06 15 Pharmacodynamics, Oximes06 15 19. ABSTRACT (Continue on reverse if necessary and identify by block number) The pharmacokinetics and

Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn.

PubMed

Giaccone, Annie; Zuppa, Athena F; Sood, Beena; Cohen, Meryl S; O'Byrne, Michael L; Moorthy, Ganesh; Mathur, Amit; Kirpalani, Haresh

2017-07-01

Objective  To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Design  Randomized, open label pilot study. Setting  Multicenter; level 3 and level 4 neonatal intensive care units. Patients  Six infants ≥34 weeks' gestational age and < 10 days of life with persistent hypoxemia receiving inhaled nitric oxide. Intervention  Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. Measurements and Main Results  The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. Conclusion  The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers.

PubMed

Gillen, Michael; Valdez, Shakti; Zhou, Dongmei; Kerr, Bradley; Lee, Caroline A; Shen, Zancong

2016-01-01

Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60-89 mL/min; N=8), moderate (eCrCl 30-59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data. Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration-time curve by 34%, 54%-65%, and 102%, respectively. Lesinurad plasma C max was unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects. Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment.

Pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxycodone transdermal patch system: a Phase I study.

PubMed

Gavin, Paul D; Simon, Lee S; Schlagheck, Thomas; Smith, Alisha J; Shakib, Sepehr

2017-07-01

To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose

Indistinguishable Synaptic Pharmacodynamics of the N-Methyl-d-Aspartate Receptor Channel Blockers Memantine and Ketamine

PubMed Central

Emnett, Christine M.; Eisenman, Lawrence N.; Taylor, Amanda M.; Izumi, Yukitoshi; Zorumski, Charles F.

2013-01-01

Memantine and ketamine, voltage- and activation-dependent channel blockers of N-methyl-d-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62% versus 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage–dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. Excitatory postsynaptic potential–like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

PubMed Central

2012-01-01

Background Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. Methods Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Results Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. Conclusions Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing. Trial registration Clinicaltrial.gov: NCT00283959 and NCT00283933 PMID:23176611

Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson's disease.

PubMed

Tolosa, E; Stern, M B

2012-02-01

Rasagiline, an MAO-B inhibitor, is indicated for the treatment of Parkinson's disease (PD). In this post hoc analysis, the efficacy, safety and tolerability of rasagiline as an adjunct to levodopa were compared with placebo in elderly (≥70 years) and younger (<70 years) patients with PD. Data were pooled from the Parkinson's Rasagiline: Efficacy and Safety on the Treatment of 'OFF' and Lasting effect in Adjunct therapy with Rasagiline Given Once daily randomized, double-blind, placebo-controlled trials with the primary efficacy end-point being the reduction from baseline in daily OFF time. Secondary efficacy end-points included scores for Clinical Global Improvement (CGI)-Examiner during ON time, Unified Parkinson's Disease Rating Scale (UPDRS)-ADL during OFF time, UPDRS-Motor during ON time and total daily ON time with and without troublesome dyskinesia. Tolerability was evaluated from adverse events (AEs) in the two age groups. Rasagiline decreased daily OFF time versus placebo (P<0.01) and improved CGI-Examiner score (P=0.001) and UPDRS-Motor ON score (P<0.05). Changes in UPDRS-ADL OFF score and total daily ON time without dyskinesia also favoured rasagiline but were not significant. Between-group comparisons (≥70 vs. <70 years) showed that efficacy was unaffected by age for all end-points (P>0.1), and rasagiline was well tolerated amongst both groups of patients with a comparable incidence of total and dopaminergic AEs (P>0.1). Adjunct rasagiline is efficacious and well tolerated in elderly non-demented patients (≥70 years) with moderate to advanced PD. Confirmation of the efficacy and safety of rasagiline in the elderly patient subgroup is especially relevant because of the increasing number of elderly patients with PD. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

PubMed

Paul, Gesine; Zachrisson, Olof; Varrone, Andrea; Almqvist, Per; Jerling, Markus; Lind, Göran; Rehncrona, Stig; Linderoth, Bengt; Bjartmarz, Hjalmar; Shafer, Lisa L; Coffey, Robert; Svensson, Mikael; Mercer, Katarina Jansson; Forsberg, Anton; Halldin, Christer; Svenningsson, Per; Widner, Håkan; Frisén, Jonas; Pålhagen, Sven; Haegerstrand, Anders

2015-03-02

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

Safety Verification of a Fault Tolerant Reconfigurable Autonomous Goal-Based Robotic Control System

NASA Technical Reports Server (NTRS)

Braman, Julia M. B.; Murray, Richard M; Wagner, David A.

2007-01-01

Fault tolerance and safety verification of control systems are essential for the success of autonomous robotic systems. A control architecture called Mission Data System (MDS), developed at the Jet Propulsion Laboratory, takes a goal-based control approach. In this paper, a method for converting goal network control programs into linear hybrid systems is developed. The linear hybrid system can then be verified for safety in the presence of failures using existing symbolic model checkers. An example task is simulated in MDS and successfully verified using HyTech, a symbolic model checking software for linear hybrid systems.

Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive.

PubMed

Ayoub, R; Page, S T; Swerdloff, R S; Liu, P Y; Amory, J K; Leung, A; Hull, L; Blithe, D; Christy, A; Chao, J H; Bremner, W J; Wang, C

2017-03-01

Dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p < 0.007) and average concentrations (p < 0.002) at the 400 mg dose, compared with the 200 mg dose. The powder formulation resulted in a lower conversion of DMAU to DMA (p = 0.027) compared with both castor oil and SEDDS formulations. DMAU in SEDDS given fasting resulted in higher serum DMA and DMAU concentrations compared to the other two formulations. Serum LH and sex hormone concentrations were suppressed by all formulations of 200 and 400 mg DMAU when administered with food, but only the SEDDS formulation was effectively suppressed serum T when given fasting. We conclude that while all three formulations of oral DMAU are effective and well tolerated when administered with food, DMAU in oil and SEDDS increased conversion to DMA, and SEDDS may have some effectiveness when given fasting. These properties might be

Pharmacokinetics, pharmacodynamics and local tolerance at injection site of marbofloxacin administered by regional intravenous limb perfusion in standing horses.

PubMed

Lallemand, Elodie; Trencart, Pierre; Tahier, Carine; Dron, Frederic; Paulin, Angelique; Tessier, Caroline

2013-08-01

To evaluate pharmacokinetic-pharmacodynamic variables and local tolerance at injection-site of marbofloxacin administered via regional intravenous limb perfusion (RIVLP) in standing horses. Adult horses (n = 6). RIVLP were performed with rubber tourniquets applied to the forelimbs of standing sedated horses. Marbofloxacin (0.67 mg/kg) was randomly injected in 1 forelimb, with the contralateral limb serving as a control (0.9% NaCl solution). Samples of jugular blood and synovial fluid from the radiocarpal joint of the marbofloxacin-perfused limb were collected before and at intervals after RIVLP for determination of drug concentrations. All injection sites were evaluated before, 24 and 48 hours after RIVLP by means of ultrasonographic examination, circumferential measurements and subjective visible inflammation scores by veterinarians unaware of treatment received. No adverse effects associated with the technique or antibiotic were observed. High marbofloxacin concentrations were obtained in the synovial fluid, AUCINF was significantly higher in synovial fluid than in plasma (78.64 ± 49.41 and 2.85 ± 0.60 µg h/mL respectively, P = .028). The efficacy indices, AUC0-24 /MIC90 and Cmaxobs/MIC90 , predicted a favorable outcome in the treatment of synovial fluid infections caused by enterobacteriaceae and Staphylococcus aureus. After RIVLP, there was no statistically significant difference between marbofloxacin-injected and control limbs for lameness, visual inflammation score, limb circumference, and ultrasonographic appearance of the veins. Marbofloxacin injected limbs had a significantly greater subcutaneous thickness, compared with control limbs. These data suggest that RIVLP of marbofloxacin (0.67 mg/kg) could be a safe and effective method for treatment of infections of the distal portion of the limb for susceptible organisms. © Copyright 2013 by The American College of Veterinary Surgeons.

Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations.

PubMed

Walter, Carmen; Knothe, Claudia; Lötsch, Jörn

2016-07-01

Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered.

Bioavailability and Pharmacodynamics of Promethazine in Human Subjects

NASA Technical Reports Server (NTRS)

Boyd, J. L.; Boster, B.; Wang, Z.; Shah, V.; Berens, K. L.; Sipes, W. E.; Anderson, K. E.; Putcha, L.

2004-01-01

The acute effects of exposure to microgravity include the development of space motion sickness, which usually requires therapeutic intervention. The current drug of choice, promethazine (PMZ), is available to astronauts in three different dosage forms during space flight; its side effects include nausea, dizziness, sedation and impaired psychomotor performance. This ground-based study is designed to validate flight-suitable methods for pharmacodynamic evaluation of PMZ and to estimate bioavailability and pharmacodynamics of PMZ. Experimental design consists of intramuscular administration of three doses of PMZ (12.5,25 and 50 mg) and placebo in a randomized double blind fashion to human subjects and collecting blood, urine and saliva samples for 72 h. Subjects also complete cognitive performance test batteries, WinSCAT (Windows based Space Cognitive Assessment Test) and ARES (ANAM Readiness Evaluation System). Preliminary results indicate a significant relationship (p=9.88e-05) between circulating PMZ levels and cognitive performance parameters. Time to accurately complete memory tasks increases significantly with concentrations; higher concentrations also increase response time and decrease accuracy of substitution and matching tasks. AUC and half-life estimates for PMZ ranged between 0.12 and 1.7 mg.h/L and 15 and 50 h, respectively. These preliminary results indicate that PMZ may exhibit dose-dependent pharmacokinetics in humans; also, WinSCAT and ARES are sensitive for pharmacodynamic assessment of PMZ, and may be applicable for assessing the pharmacodynamics of other neurocognitive drugs.

Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity.

PubMed

Marzo, Antonio; Dal Bo, Lorenzo; Monti, Nunzia Ceppi; Crivelli, Fabrizio; Ismaili, Shevqet; Caccia, Carla; Cattaneo, Carlo; Fariello, Ruggero G

2004-07-01

This paper describes the pharmacokinetics and the pharmacodynamics, in terms of monoamino oxidase type B (MAO-B) inhibition, in male healthy volunteers of orally administered safinamide, a new neuroprotectant that in experimental models has demonstrated strong anticonvulsant and antiparkinson activities. Four clinical trials covering the dose range of 25-10,000 microg/kg were carried out to describe pharmacokinetics, pharmacodynamics and tolerability of safinamide, administered in single or repeated dose regimen to steady state, including a food interaction trial. All the above trials were carried out after the Ethics Committee's approval and signature of the consent form by the volunteers. In single dose trials blood sampling covered a 24 h-period in pharmacodynamic trials, 48 h-period in pharmacokinetic trials. In the case of repeated dose regimen to steady state a pre-dose sample was drawn on the first six study days, whereas the curve was explored on the 7th study day, prolonging blood sampling over a 48 h-period after the last dosing. Safinamide level was determined in plasma by a very sensitive and specific LC-MS-MS method, with a low limit of quantification of 0.5 ng/ml of plasma. Pharmacokinetic analysis was carried out with non-compartmental method and, in one case, also with the two-compartmental method. Monoamine oxidase activity of both types A and B (MAO-A and MAO-B) was determined in plasma at different times (MAO-B) and correlated to safinamide levels, or in urine (MAO-A). Pharmacokinetics of safinamide proved to be linearly and proportionally related to the administered doses. The absorption of safinamide was rapid with peak plasma concentrations ranging from 2 to 4 h. Food prolonged the rate and did not affect the extent of absorption of safinamide. In repeat dose regimen once daily, the steady state was reached on the 5th study day with a marginal accumulation factor of 1.5-1.7. The drug was cleared with a t(1/2) of about 22 h. Safinamide

Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.

PubMed

Parry, Gareth J; Rodrigues, Cecilia M P; Aranha, Marcia M; Hilbert, Sarah J; Davey, Cynthia; Kelkar, Praful; Low, Walter C; Steer, Clifford J

2010-01-01

Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

Reactor Safety Gap Evaluation of Accident Tolerant Components and Severe Accident Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farmer, Mitchell T.; Bunt, R.; Corradini, M.

The overall objective of this study was to conduct a technology gap evaluation on accident tolerant components and severe accident analysis methodologies with the goal of identifying any data and/or knowledge gaps that may exist, given the current state of light water reactor (LWR) severe accident research, and additionally augmented by insights obtained from the Fukushima accident. The ultimate benefit of this activity is that the results can be used to refine the Department of Energy’s (DOE) Reactor Safety Technology (RST) research and development (R&D) program plan to address key knowledge gaps in severe accident phenomena and analyses that affectmore » reactor safety and that are not currently being addressed by the industry or the Nuclear Regulatory Commission (NRC).« less

Safety and Tolerability of Atomoxetine over 3 to 4 Years in Children with ADHD

ERIC Educational Resources Information Center

Donnelly, Craig; Bangs, Mark; Trzepacz, Paula; Jin, Ling; Zhang, Shuyu; Witte, Michael M.; Ball, Susan G.; Spencer, Thomas J.

2009-01-01

Data from 13 double-blind, placebo-controlled trials and three open-label extension studies were pooled to examine the safety of atomoxetine for treating attention deficit hyperactivity disorder in children and adolescents for less than or equal to three or four years. Results show that atomoxetine is safe and well tolerated in the subjects.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients

PubMed Central

Paul, Gesine; Zachrisson, Olof; Varrone, Andrea; Almqvist, Per; Jerling, Markus; Lind, Göran; Rehncrona, Stig; Linderoth, Bengt; Bjartmarz, Hjalmar; Shafer, Lisa L.; Coffey, Robert; Svensson, Mikael; Mercer, Katarina Jansson; Forsberg, Anton; Halldin, Christer; Svenningsson, Per; Widner, Håkan; Frisén, Jonas; Pålhagen, Sven; Haegerstrand, Anders

2015-01-01

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson’s disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA). PMID:25689258

Efficacy, Safety, and Tolerability of Armodafinil Therapy for Hypersomnia Associated With Dementia With Lewy Bodies: A Pilot Study

PubMed Central

Lapid, Maria I.; Kuntz, Karen M.; Mason, Sara S.; Aakre, Jeremiah A.; Lundt, Emily S.; Kremers, Walter; Allen, Laura A.; Drubach, Daniel A.; Boeve, Bradley F.

2017-01-01

Background/Aims Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB. Methods We performed a 12-week pilot trial of armodafinil therapy (125–250 mg orally daily) in DLB outpatients with hypersomnia. Patients underwent neurologic examinations, neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method. Results Of 20 participants, 17 completed the protocol. Median age was 72 years, most were men (80%), and most had spouses as caregivers. Epworth Sleepiness Scale (P<.001), Maintenance of Wakefulness Test (P=.003), and Clinical Global Impression of Change (P<.001) scores improved at week 12. Neuropsychiatric Inventory total score (P=.003), visual hallucinations (P=.003), and agitation (P=.02) improved at week 4. Caregiver overall quality of life improved at week 12 (P=.004). No adverse events occurred. Conclusion These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies to manage hypersomnolence in these patients. PMID:28448998

Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse.

PubMed

Roberts, John C; Grocholski, Brent M; Kitto, Kelley F; Fairbanks, Carolyn A

2005-09-01

Agmatine is an endogenous decarboxylation product of arginine that has been previously shown to antagonize the N-methyl-d-aspartate (NMDA) receptor and inhibit nitric-oxide synthase. Many neuropharmacological studies have shown that exogenous administration of agmatine prevents or reverses biological phenomena dependent on central nervous system glutamatergic systems, including opioid-induced tolerance, opioid self-administration, and chronic pain. However, the central nervous system (CNS) pharmacokinetic profile of agmatine remains minimally defined. The present study determined the spinal cord pharmacokinetics and acute pharmacodynamics of intrathecally administered agmatine in mice. After a single bolus intrathecal injection, agmatine concentrations in spinal cord (cervical, thoracic, and lumbosacral) tissue and serum were quantified by an isocratic high-performance liquid chromatography fluorescence detection system. Agmatine persisted at near maximum concentrations in all levels of the spinal cord for several hours with a half-life of approximately 12 h. Initial agmatine concentrations in serum were 10% those in CNS. However, the serum half-life was less than 10 min after intrathecal injection of agmatine, consistent with previous preliminary pharmacokinetic reports of systemically administered agmatine. The pharmacodynamic response to agmatine in the NMDA-nociceptive behavior and thermal hyperalgesia tests was assessed. Whereas MK-801 (dizocilpine maleate) inhibits these two responses with equal potency, agmatine inhibits the thermal hyperalgesia with significantly increased potency compared with the nociceptive behavior, suggesting two sites of action. In contrast to the pharmacokinetic results, the agmatine inhibition of both behaviors had a duration of only 10 to 30 min. Collectively, these results suggest the existence of a currently undefined agmatinergic extracellular clearance process in spinal cord.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.

PubMed

Creelan, Ben C; Gabrilovich, Dmitry I; Gray, Jhanelle E; Williams, Charles C; Tanvetyanon, Tawee; Haura, Eric B; Weber, Jeffrey S; Gibney, Geoffrey T; Markowitz, Joseph; Proksch, Joel W; Reisman, Scott A; McKee, Mark D; Chin, Melanie P; Meyer, Colin J; Antonia, Scott J

2017-01-01

Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

Pharmacokinetic/pharmacodynamic modeling of psychomotor impairment induced by oral clonazepam in healthy volunteers.

PubMed

dos Santos, Fábio Monteiro; Gonçalves, José Carlos Saraiva; Caminha, Ricardo; da Silveira, Gabriel Estolano; Neves, Claúdia Silvana de Miranda; Gram, Karla Regina da Silva; Ferreira, Carla Teixeira; Jacqmin, Philippe; Noël, François

2009-10-01

This study was undertaken to model the relationship between clonazepam plasma concentrations and a central nervous system adverse effect (impairment of the psychomotor performance) following the oral administration of immediate-release tablets of clonazepam in healthy volunteers. Such a (P)pharmacokinetic/(P)pharmacodynamic (PK/PD) study is important to interpret properly the consequences of determined levels of plasma concentrations of psychoactive therapeutic drugs reported to be involved in road-traffic accidents. Twenty-three male subjects received a single oral dose of 4 mg clonazepam. Plasma concentration, determined by on-line solid phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry, and psychomotor performance, quantified through the Digit Symbol Substitution Test, were monitored for 72 hours. A 2-compartment open model with first order absorption and lag-time better fitted the plasma clonazepam concentrations. Clonazepam decreased the psychomotor performance by 72 +/- 3.7% (observed maximum effect), 1.5 to 4 hours (25th-75th percentile) after drug administration. A simultaneous population PK/PD model based on a sigmoid Emax model with time-dependent tolerance described well the time course of effect. Such acute tolerance could minimize the risk of accident as a result of impairment of motor skill after a single dose of clonazepam. However, an individual analysis of the data revealed a great interindividual variation in the relationship between clonazepam effect and plasma concentration, indicating that the phenomenon of acute tolerance can be predicted at a population, but not individual, level.

Abuse Tolerance Improvements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orendorff, Christopher J.; Nagasubramanian, Ganesan; Fenton, Kyle R.

As lithium-ion battery technologies mature, the size and energy of these systems continues to increase (> 50 kWh for EVs); making safety and reliability of these high energy systems increasingly important. While most material advances for lithium-ion chemistries are directed toward improving cell performance (capacity, energy, cycle life, etc.), there are a variety of materials advancements that can be made to improve lithium-ion battery safety. Issues including energetic thermal runaway, electrolyte decomposition and flammability, anode SEI stability, and cell-level abuse tolerance continue to be critical safety concerns. This report highlights work with our collaborators to develop advanced materials to improvemore » lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.« less

Pharmacodynamics of nicotine: implications for rational treatment of nicotine addiction.

PubMed

Benowitz, N L

1991-05-01

Rational treatment of the pharmacologic aspects of tobacco addiction includes nicotine substitution therapy. Understanding the pharmacodynamics of nicotine and its role in the addiction process provides a basis for rational therapeutic intervention. Pharmacodynamic considerations are discussed in relation to the elements of smoking cessation therapy: setting objectives, selecting appropriate medication and dosing form, selecting the optimal doses and dosage regimens, assessing therapeutic outcome, and adjusting therapy to optimize benefits and minimize risks.

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus.

PubMed

Vajda, Eric G; Logan, Douglas; Lasseter, Kenneth; Armas, Danielle; Plotkin, Diane J; Pipkin, J D; Li, Yong-Xi; Zhou, Rong; Klein, David; Wei, Xiaoxiong; Dilzer, Stacy; Zhi, Lin; Marschke, Keith B

2017-01-01

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD-6972, in healthy subjects and subjects with type 2 diabetes (T2DM). In the single ascending dose study, LGD-6972 (2-480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia. Inhibition of glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs.

PubMed

Shen, Chenlin; Huang, Xiaohui; Li, Jun; Zhang, Ping; Li, Lin; Zhang, Wei; Hu, Tingting; Pappoe, Faustina; Huang, Jihan; Tang, Haiqin

2016-01-01

1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin-aspirin therapy, the safety and side effect of combined therapy remains unclear. 2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses. 3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC(0-t)) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC(0-t) and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC(0-t) and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin. 4. Coadministration of warfarin had no markedly effects on the AUC(0-t) and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC(0-t) and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin. 5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug-drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin-aspirin drug interactions in healthy volunteers or patients.

Safety and tolerability of bilastine 10 mg administered for 12 weeks in children with allergic diseases.

PubMed

Novák, Zoltán; Yáñez, Anahí; Kiss, Ildikó; Kuna, Piotr; Tortajada-Girbés, Miguel; Valiente, Román

2016-08-01

Regulations on medicinal products for paediatric use require that pharmacokinetics and safety be characterized specifically in the paediatric population. A previous study established that a 10-mg dose of bilastine in children aged 2 to <12 years provided an equivalent systemic exposure as 20 mg in adults. The current study assessed the safety and tolerability of bilastine 10 mg in children with allergic rhinoconjunctivitis and chronic urticaria. In this phase III, multicentre, double-blind study, children were randomized to once-daily treatment with bilastine 10-mg oral dispersible table (n = 260) or placebo (n = 249) for 12 weeks. Safety evaluations included treatment-emergent adverse events (TEAEs), laboratory tests, cardiac safety (ECG recordings) and somnolence/sedation using the Pediatric Sleep Questionnaire (PSQ). The primary hypothesis of non-inferiority between bilastine 10 mg and placebo was demonstrated on the basis of a near-equivalent proportion of children in each treatment arm without TEAEs during 12 weeks' treatment (31.5 vs. 32.5%). No clinically relevant differences between bilastine 10 mg and placebo were observed from baseline to study end for TEAEs or related TEAEs, ECG parameters and PSQ scores. The majority of TEAEs were mild or moderate in intensity. TEAEs led to discontinuation of two patients treated with bilastine 10 mg and one patient treated with placebo. Bilastine 10 mg had a safety and tolerability profile similar to that of placebo in children aged 2 to <12 years with allergic rhinoconjunctivitis or chronic urticaria. © 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.

Safety and tolerability review of lorcaserin in clinical trials.

PubMed

Greenway, F L; Shanahan, W; Fain, R; Ma, T; Rubino, D

2016-10-01

Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations. © 2016 World Obesity.

An Algorithm and R Program for Fitting and Simulation of Pharmacokinetic and Pharmacodynamic Data.

PubMed

Li, Jijie; Yan, Kewei; Hou, Lisha; Du, Xudong; Zhu, Ping; Zheng, Li; Zhu, Cairong

2017-06-01

Pharmacokinetic/pharmacodynamic link models are widely used in dose-finding studies. By applying such models, the results of initial pharmacokinetic/pharmacodynamic studies can be used to predict the potential therapeutic dose range. This knowledge can improve the design of later comparative large-scale clinical trials by reducing the number of participants and saving time and resources. However, the modeling process can be challenging, time consuming, and costly, even when using cutting-edge, powerful pharmacological software. Here, we provide a freely available R program for expediently analyzing pharmacokinetic/pharmacodynamic data, including data importation, parameter estimation, simulation, and model diagnostics. First, we explain the theory related to the establishment of the pharmacokinetic/pharmacodynamic link model. Subsequently, we present the algorithms used for parameter estimation and potential therapeutic dose computation. The implementation of the R program is illustrated by a clinical example. The software package is then validated by comparing the model parameters and the goodness-of-fit statistics generated by our R package with those generated by the widely used pharmacological software WinNonlin. The pharmacokinetic and pharmacodynamic parameters as well as the potential recommended therapeutic dose can be acquired with the R package. The validation process shows that the parameters estimated using our package are satisfactory. The R program developed and presented here provides pharmacokinetic researchers with a simple and easy-to-access tool for pharmacokinetic/pharmacodynamic analysis on personal computers.

Efficacy and safety of biosimilar insulins compared to their reference products: A systematic review.

PubMed

Tieu, Carolyn; Lucas, Eleanor J; DePaola, Mindi; Rosman, Lori; Alexander, G Caleb

2018-01-01

For nearly a century, no generic form of insulin has been available in the United States. However, the first biosimilar insulin, Basaglar, was approved by the U.S. Food and Drug Administration in 2015, and subsequently Admelog and Lusduna in 2017. To summarize the scientific evidence comparing the safety, efficacy, pharmacokinetics, and pharmacodynamics of biosimilar and reference insulin products. We conducted a systematic review using PubMed, Cochrane, Embase, Latin America and Caribbean Health Sciences, South Asian Database of Controlled Clinical Trials, and IndiaMED from their inception through January 14, 2018. We included randomized controlled trials (RCTs) comparing safety, clinical efficacy, pharmacokinetics and pharmacodynamics of any biosimilar insulin with a reference product in adults regardless of sample size and location. Two researchers independently reviewed all titles, abstracts and text; extracted data; and performed quality assessments. Efficacy, safety, pharmacokinetics, and pharmacodynamics of biosimilar and reference insulin products. Of 6945 articles screened, 11 studies were included in the data synthesis. LY2963016, Basalog, Basalin, and MK-1293 were compared to Lantus while SAR342434 was compared to Humalog. Three trials enrolled healthy volunteers, five enrolled type 1 diabetics, and two enrolled type 2 diabetics. One study enrolled both healthy and type 1 diabetics. Of the eleven studies, six examined pharmacokinetic and/or pharmacodynamic parameters and five examined clinical efficacy and immunogenicity. All studies included adverse events. All PK and/or PD studies showed that comparable parameters of biosimilar and reference products were within the pre-specified equivalence margins. Clinical studies suggested similar clinical efficacy and immunogenicity. Adverse events were similar between the groups across all studies. Few published studies have compared biosimilar and reference insulins, though those that did suggest that the

Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study

PubMed Central

Shepshelovich, Daniel; Edel, Yonatan; Goldvaser, Hadar; Dujovny, Tal; Wolach, Ofir; Raanani, Pia

2015-01-01

AIMS Cytarabine is a pyrimidine analogue used to treat a variety of haematological malignancies. There are few data regarding the pharmacodynamics of cytarabine. The only publications regarding this issue cite a biphasic pattern of decline in white blood cell (WBC) counts following low and intermediate doses, in patients with various malignancies, most of them non-haematological. Our purpose was to establish the pharmacodynamics of cytarabine induced leucopenia in acute myeloid leukaemia (AML) patients treated with contemporary cytarabine containing protocols. METHODS We conducted a retrospective cohort study, including 56 patients with AML in complete remission who had received 89 cycles of intermediate or high dose cytarabine. Daily counts for WBCs and neutrophils (ANC) were collected during the first 15 days after the initiation of cytarabine administration and pharmacodynamics were analyzed. Further analysis was carried out to correlate between WBC and ANC pharmacodynamics and different cytarabine protocols [high dose cytarabine (HiDAC) vs. intermediate dose cytarabine (IDAC)]. RESULTS Analysis of blood counts demonstrated a monophasic decline of WBCs and ANCs, unlike a previous depiction of a biphasic pattern. HiDAC was associated with a significantly sharper decline of WBCs than IDAC. CONCLUSIONS Our data support a monophasic decline pattern of WBCs and ANCs following contemporary cytarabine protocols. The decline rate is steeper for patients receiving HiDAC than for those receiving IDAC. These results might help form evidence based guidelines regarding patient monitoring intensity, timing of prophylactic antibacterial and antifungal treatment as well as growth factors' support following cytarabine based consolidation for AML. PMID:25303309

Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study.

PubMed

Shepshelovich, Daniel; Edel, Yonatan; Goldvaser, Hadar; Dujovny, Tal; Wolach, Ofir; Raanani, Pia

2015-04-01

Cytarabine is a pyrimidine analogue used to treat a variety of haematological malignancies. There are few data regarding the pharmacodynamics of cytarabine. The only publications regarding this issue cite a biphasic pattern of decline in white blood cell (WBC) counts following low and intermediate doses, in patients with various malignancies, most of them non-haematological. Our purpose was to establish the pharmacodynamics of cytarabine induced leucopenia in acute myeloid leukaemia (AML) patients treated with contemporary cytarabine containing protocols. We conducted a retrospective cohort study, including 56 patients with AML in complete remission who had received 89 cycles of intermediate or high dose cytarabine. Daily counts for WBCs and neutrophils (ANC) were collected during the first 15 days after the initiation of cytarabine administration and pharmacodynamics were analyzed. Further analysis was carried out to correlate between WBC and ANC pharmacodynamics and different cytarabine protocols [high dose cytarabine (HiDAC) vs. intermediate dose cytarabine (IDAC)]. Analysis of blood counts demonstrated a monophasic decline of WBCs and ANCs, unlike a previous depiction of a biphasic pattern. HiDAC was associated with a significantly sharper decline of WBCs than IDAC. Our data support a monophasic decline pattern of WBCs and ANCs following contemporary cytarabine protocols. The decline rate is steeper for patients receiving HiDAC than for those receiving IDAC. These results might help form evidence based guidelines regarding patient monitoring intensity, timing of prophylactic antibacterial and antifungal treatment as well as growth factors' support following cytarabine based consolidation for AML. © 2014 The British Pharmacological Society.

Tolerance and safety of superficial chemical peeling with salicylic acid in various facial dermatoses.

PubMed

Bari, Arfan Ul; Iqbal, Zafar; Rahman, Simeen Ber

2005-01-01

Chemical peeling is a skin-wounding procedure that may have some potentially undesirable side-effects. The present study is directed towards safety concerns associated with superficial chemical peeling with salicylic acid in various facial dermatoses. The study was a non-comparative and a prospective one. Two hundred and sixty-eight patients of either sex, aged between 10 to 60 years, undergoing superficial chemical peeling for various facial dermatoses (melasma, acne vulgaris, freckles, post-inflammatory scars/pigmentation, actinic keratoses, plane facial warts, etc.) were included in the study. Eight weekly peeling sessions were carried out in each patient. Tolerance to the procedure and any undesirable effects noted during these sessions were recorded. Almost all the patients tolerated the procedure well. Mild discomfort, burning, irritation and erythema were quite common but the incidence of major side-effects was very low and these too, were easily manageable. There was no significant difference in the incidence of side-effects between facial dermatoses (melasma, acne and other pigmentary disorders). Chemical peeling with salicylic acid is a well tolerated and safe treatment modality in many superficial facial dermatoses.

Pharmacokinetics, safety and tolerability of rotigotine transdermal patch in healthy Japanese and Caucasian subjects.

PubMed

Cawello, Willi; Kim, Seong R; Braun, Marina; Elshoff, Jan-Peer; Ikeda, Junji; Funaki, Tomoo

2014-02-01

Rotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson's disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration-time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values). The pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0±0.5 mg for Japanese subjects and 2.08±0.58 mg for Caucasians. Plasma concentration-time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after

Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles

NASA Astrophysics Data System (ADS)

Kang, Homan; Mintri, Shrutika; Menon, Archita Venugopal; Lee, Hea Yeon; Choi, Hak Soo; Kim, Jonghan

2015-11-01

Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodynamic efficacy and toxicity of NPs. Although theranostic NPs hold great promise in nanomedicine and biomedical applications, a lack of understanding persists on the mechanisms of the biodistribution and adverse effects of NPs. To better understand the diagnostic and therapeutic functions of NPs, this review discusses the factors that influence the pharmacokinetics, pharmacodynamics and toxicology of theranostic NPs, along with several strategies for developing novel diagnostic and therapeutic modalities.

Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes.

PubMed

Strange, P; Schwartz, S L; Graf, R J; Polvino, W; Weston, I; Marbury, T C; Huang, W C; Goldberg, R B

1999-01-01

The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes. Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean). Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events. These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.

Population Pharmacokinetic-Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats.

PubMed

Kobuchi, Shinji; Ito, Yukako; Sakaeda, Toshiyuki

2017-08-01

Myelosuppression is a dose-limiting toxicity of 5-fluorouracil (5-FU). Predicting the inter- and intra-patient variability in pharmacokinetics and toxicities of 5-FU may contribute to the individualized medicine. This study aimed to establish a population pharmacokinetic-pharmacodynamic model that could evaluate the inter- and intra-individual variability in the plasma 5-FU concentration, 5-FU-induced body weight loss and myelosuppression in rats. Plasma 5-FU concentrations, body weight loss, and blood cell counts in rats following the intravenous administration of various doses of 5-FU for 4 days were used to develop the population pharmacokinetic-pharmacodynamic model. The population pharmacokinetic model consisting of a two-compartment model with Michaelis-Menten elimination kinetics successfully characterized the individual and population predictions of the plasma concentration of 5-FU and provided credible parameter estimates. The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively. The population pharmacokinetic-pharmacodynamic model adequately described the individual complete time-course of alterations in body weight loss, erythrocyte, leukocyte, and lymphocyte counts in rats treated with various doses of 5-FU. The inter-individual variability of the drug effects in the pharmacodynamic model for body weight loss was 82.6%, which was relatively high. The results of the present study suggest that not only individual fluctuations in the 5-FU concentration but also the cell sensitivity would affect the onset and degree of 5-FU-induced toxicity. This population pharmacokinetic-pharmacodynamic model could evaluate the inter- and intra-individual variability in drug-induced toxicity and guide the assessments of novel anticancer agents in drug development.

Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data.

PubMed

Cicero, Arrigo F G; Tartagni, Elisa; Ertek, Sibel

2014-08-01

To answer the need of a better low-density lipoprotein (LDL) cholesterol control in statin-treated patients at high risk for cardiovascular disease, new injectable lipid-lowering drugs with innovative mechanisms of action are in advanced phase of development or have just been approved. Evolocumab and alirocumab are fully human monoclonal antibodies inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) that binds to hepatic LDL receptor and prevents it from normal recycling by targeting it for degradation. Mipomersen specifically binds to a segment of the human apolipoprotein B100 messenger RNA, blocking the translation of the gene product. Phase II (for evolocumab and alirocumab) and III (for evolocumab) trials show that PCSK9 inhibitors are equally well tolerated, with adverse events mainly limited to mild-to-moderate nasopharyngitis, injection-site pain, arthralgia and back pain. Mipomersen use is mainly associated to hepatosteatosis, increased transaminases (> 3 times the upper limit of normal), mild-to-moderate injection-site reactions and flu-like symptoms. PCSK9 inhibitors have demonstrated their good safety and tolerability in a large number of subjects with different clinical conditions, including statin-intolerance, enlarging their potential use in a broader range of patients. Further data on long-term mipomersen safety are required.

Pharmacokinetics and pharmacodynamics of intravenous levofloxacin at 750 milligrams and various doses of metronidazole in healthy adult subjects.

PubMed

Sprandel, Kelly A; Schriever, Christopher A; Pendland, Susan L; Quinn, John P; Gotfried, Mark H; Hackett, Suzanne; Graham, Mary Beth; Danziger, Larry H; Rodvold, Keith A

2004-12-01

regimens of levofloxacin and metronidazole were well tolerated, and no serious drug-related adverse effects were reported. The pharmacokinetic, safety, and pharmacodynamic data from our study suggest that a once-daily regimen of intravenous levofloxacin at 750 mg and metronidazole at 1,500 mg warrants further clinical investigation.

Pharmacokinetics and Pharmacodynamics of Intravenous Levofloxacin at 750 Milligrams and Various Doses of Metronidazole in Healthy Adult Subjects

PubMed Central

Sprandel, Kelly A.; Schriever, Christopher A.; Pendland, Susan L.; Quinn, John P.; Gotfried, Mark H.; Hackett, Suzanne; Graham, Mary Beth; Danziger, Larry H.; Rodvold, Keith A.

2004-01-01

regimens of levofloxacin and metronidazole were well tolerated, and no serious drug-related adverse effects were reported. The pharmacokinetic, safety, and pharmacodynamic data from our study suggest that a once-daily regimen of intravenous levofloxacin at 750 mg and metronidazole at 1,500 mg warrants further clinical investigation. PMID:15561831

A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film.

PubMed

Bunge, Katherine E; Dezzutti, Charlene S; Rohan, Lisa C; Hendrix, Craig W; Marzinke, Mark A; Richardson-Harman, Nicola; Moncla, Bernard J; Devlin, Brid; Meyn, Leslie A; Spiegel, Hans M L; Hillier, Sharon L

2016-04-15

Films may deliver antiretroviral drugs efficiently to mucosal tissues. In this first in-human trial of a vaginal film for delivering the nonnucleoside reverse transcriptase inhibitor dapivirine, safety, pharmacokinetics, and pharmacodynamics of film and gel formulations were compared with placebo. Sixty-one healthy HIV-negative women were randomized to daily dapivirine (0.05%) or placebo gel, or dapivirine (1.25 mg) or placebo film for seven days. The proportion of participants experiencing grade 2 and higher adverse events related to study product were compared. Plasma dapivirine concentrations were quantified. Paired cervical and vaginal tissue biopsies obtained ∼2 hours after the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay. Two grade 2 related adverse events occurred in the placebo film group. Women randomized to gel and film products had 4 log10 higher of dapivirine in cervical and vaginal tissues than plasma. Although gel and film users had comparable plasma dapivirine concentrations, tissue concentrations of dapivirine were 3-5 times higher in the gel users when compared with film users. HIV replication in the ex vivo challenge assay was significantly reduced in vaginal tissues from women randomized to dapivirine film or gel; furthermore, tissue drug concentrations were highly correlated with HIV protection. Women rated the film more comfortable with less leakage but found it more difficult to insert than gel. Both film and gel delivered dapivirine at concentrations sufficient to block HIV ex vivo. This proof-of-concept study suggests film formulations for microbicides merit further investigation.

A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of a novel dapivirine vaginal film

PubMed Central

Bunge, Authors: Katherine E.; Dezzutti, Charlene S.; Rohan, Lisa C.; Hendrix, Craig W.; Marzinke, Mark A.; Richardson-Harman, Nicola; Moncla, Bernard J.; Devlin, Brid; Meyn, Leslie A.; M.L.Spiegel, Hans; Hillier, Sharon L.

2016-01-01

Background Films may deliver antiretroviral drugs efficiently to mucosal tissues. In this first in-human trial of a vaginal film for delivering the non-nucleoside reverse transcriptase inhibitor dapivirine, safety, pharmacokinetics, and pharmacodynamics of film and gel formulations were compared to placebo. Methods 61 healthy HIV negative women were randomized to daily dapivirine (0.05%) or placebo gel, or dapivirine (1.25mg) or placebo film for seven days. The proportion of participants experiencing Grade 2 and higher adverse events related to study product were compared. Plasma dapivirine concentrations were quantified. Paired cervical and vaginal tissue biopsies obtained ∼2 hours following the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay. Results Two Grade 2 related AEs occurred in the placebo film group. Women randomized to gel and film products had 4 log10 higher of dapivirine in cervical and vaginal tissues than plasma. While gel and film users had comparable plasma dapivirine concentrations, tissue concentrations of dapivirine were 3 to 5 times higher in the gel users when compared to film users. HIV replication in the ex vivo challenge assay was significantly reduced in vaginal tissues from women randomized to dapivirine film or gel; furthermore, tissue drug concentrations were highly correlated with HIV protection. Women rated the film more comfortable with less leakage, but found it more difficult to insert than gel. Discussion Both film and gel delivered dapivirine at concentrations sufficient to block HIV ex vivo. This proof of concept study suggests film formulations for microbicides merit further investigation. PMID:26565716

A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Single Enantiomer (+)-Mefloquine Compared with Racemic Mefloquine in Healthy Persons

PubMed Central

Tansley, Robert; Lotharius, Julie; Priestley, Anthony; Bull, Fiona; Duparc, Stephan; Möhrle, Jörg

2010-01-01

Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (−) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (−)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted. PMID:21118921

Effect of personality type on pharmacodynamics through changing pharmacokinetics.

PubMed

Xu, Feng

2007-01-01

A few studies have showed that there is an association between the genetic polymorphisms of drug-metabolizing enzyme, CYP2D6, to persons with different personality type. More and more evidences suggested that personality type is kind of behavioral or psychological factor which might influence the pharmacodynamics as well as patient's gender, age, disease, and genetic background. We hypothesized that personality affect the pharmacodynamics through changing pharmacokinetic mediated by different polymorphism of drug-metabolizing enzymes. Since many major diseases, from cancer to infectious disease, are involved with risky Type A personality, we appeal for attention to the clinical pharmacologist and psychiatrists further to study personality pharmacokinetics for individualized medicine.

A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.

The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the developmentmore » and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.« less

Pharmacokinetic and pharmacodynamic assessment of bioavailability for two prodrugs of methylprednisolone

PubMed Central

Daley-Yates, P. T.; Gregory, A. J.; Brooks, C. D.

1997-01-01

Aims The aim of this study was to establish whether pharmacokinetic differences between two pro-drugs of methylprednisolone (MP) are likely to be of clinical significance. Methods This study was a single-blind, randomized, crossover design comparing the bioequivalence of MP released from the pro-drugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) after a single 250 mg (MP equivalent) intramuscular injection to 20 healthy male volunteers. Bioequivalence was assessed by conventional pharmacokinetic analysis, by measuring pharmacodynamic responses plus a novel approach using pharmacokinetic/pharmacodynamic modeling. The main measure of pharmacodynamic response was whole blood histamine (WBH), a measure of basophil numbers. Results The MP Cmax was less for MP suleptanate due to a longer absorption half-life of the prodrug from the intramuscular injection site. The bioavailability of MP was equivalent when based on AUC with a MP suleptanate median 108% of the MP succinate value (90% CI: 102–114%). For Cmax the MP suleptanate median was 81% of the MP succinate value (90% CI: 75–88%). The tmax for MP from MP suleptanate was delayed relative to MP succinate. The median difference was 200% (90% non-parametric CI: 141–283%). The area under the WBH effect-time curve (AUEC) and the maximum response (Emax ) were found to be equivalent (90% CI: 98–113% and 93–109% respectively). The maximum changes in other white blood cell counts, blood glucose concentration and the parameters of the pharmacodynamic sigmoid Emax model (EC50, Emax and γ) were also not significantly different between prodrugs. Conclusions MP suleptanate is an acceptable pharmaceutical alternative to MP succinate. The use of both pharmacokinetic and pharmacodynamic response data together gives greater confidence in the conclusions compared with those based only on conventional pharmacokinetic bioequivalence analysis. PMID:9205819

Tolerability and safety of the intake of bovine milk oligosaccharides extracted from cheese whey in healthy human adults.

PubMed

Smilowitz, Jennifer T; Lemay, Danielle G; Kalanetra, Karen M; Chin, Elizabeth L; Zivkovic, Angela M; Breck, Melissa A; German, J Bruce; Mills, David A; Slupsky, Carolyn; Barile, Daniela

2017-01-01

Mechanistic research suggests a unique evolutionary relationship between complex milk oligosaccharides and cognate bifidobacteria enriched in breast-fed infants. Bovine milk oligosaccharides (BMO) were recently identified as structurally and functionally similar to human milk oligosaccharides. The present single-blind three-way crossover study is the first to determine the safety and tolerability of BMO consumption by healthy human participants ( n 12) and its effects on faecal microbiota and microbial metabolism. Participants consumed each supplement (placebo-control; low- and high-BMO doses) for eleven consecutive days, followed by a 2-week washout period prior to initiating the next supplement arm. Low and high BMO doses were consumed as 25 and 35 % of each individual's daily fibre intake, respectively. Safety and tolerability were measured using standardised questionnaires on gut and stomach discomfort and stool consistency. Faecal extracts were profiled for bacterial populations by next-generation sequencing (NGS) and bifidobacteria presence was confirmed using quantitative PCR. Urine was analysed for changes in microbial metabolism using nuclear magnetic resonance spectroscopy ( 1 H-NMR). Consumption of both the low and high BMO doses was well tolerated and did not change stool consistency from baseline. Multivariate analysis of the NGS results demonstrated no change in faecal microbiota phyla among the placebo-control and BMO supplement groups. In conclusion, BMO supplementation was well tolerated in healthy adults and has the potential to shift faecal microbiota toward beneficial strains as part of a synbiotic treatment with probiotic cultures that selectively metabolise oligosaccharides.

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

PubMed Central

Cranston, Ross D.; Kashuba, Angela; Hendrix, Craig W.; Bumpus, Namandjé N.; Richardson-Harman, Nicola; Elliott, Julie; Janocko, Laura; Khanukhova, Elena; Dennis, Robert; Cumberland, William G.; Ju, Chuan; Carballo-Diéguez, Alex; Mauck, Christine; McGowan, Ian

2012-01-01

Abstract This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use “if somewhat protective” was ∼75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) Cmax 30 min after single rectal exposure was 6–10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK–PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK–PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations. PMID:22943559

Fractional dynamics pharmacokinetics–pharmacodynamic models

PubMed Central

2010-01-01

While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics–pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior. The families represent extensions of frequently used PK link and PD direct and indirect action models, using the tools of fractional calculus. In addition the PD models can be a function of a variable, the active drug, which can smoothly transition from concentration to exposure, to hyper-exposure, according to a fractional integral transformation. To investigate the behavior of the models we propose, we implement numerical algorithms for fractional integration and for the numerical solution of a system of fractional differential equations. For simplicity, in our investigation we concentrate on the pharmacodynamic side of the models, assuming standard (integer order) pharmacokinetics. PMID:20455076

Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C.

PubMed

German, Polina; Mathias, Anita; Brainard, Diana; Kearney, Brian P

2016-11-01

Ledipasvir/sofosbuvir (Harvoni ® ), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, ledipasvir reaches maximum plasma concentrations (T max ) 4-4.5 h post-dose and is eliminated with a terminal half-life (t 1/2 ) of 47 h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma (T max : 0.8-1 h; t 1/2 : 0.5 h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4 h post-dose; the elimination t 1/2 for GS-331007 is 27 h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for ledipasvir/sofosbuvir.

A Conceptual Framework for Pharmacodynamic Genome-wide Association Studies in Pharmacogenomics

PubMed Central

Wu, Rongling; Tong, Chunfa; Wang, Zhong; Mauger, David; Tantisira, Kelan; Szefler, Stanley J.; Chinchilli, Vernon M.; Israel, Elliot

2013-01-01

Summary Genome-wide association studies (GWAS) have emerged as a powerful tool to identify loci that affect drug response or susceptibility to adverse drug reactions. However, current GWAS based on a simple analysis of associations between genotype and phenotype ignores the biochemical reactions of drug response, thus limiting the scope of inference about its genetic architecture. To facilitate the inference of GWAS in pharmacogenomics, we sought to undertake the mathematical integration of the pharmacodynamic process of drug reactions through computational models. By estimating and testing the genetic control of pharmacodynamic and pharmacokinetic parameters, this mechanistic approach does not only enhance the biological and clinical relevance of significant genetic associations, but also improve the statistical power and robustness of gene detection. This report discusses the general principle and development of pharmacodynamics-based GWAS, highlights the practical use of this approach in addressing various pharmacogenomic problems, and suggests that this approach will be an important method to study the genetic architecture of drug responses or reactions. PMID:21920452

Carbamazepine toxicity during combination therapy with levetiracetam: a pharmacodynamic interaction.

PubMed

Sisodiya, Sanjay M; Sander, Josemir W A S; Patsalos, Philip N

2002-02-01

Levetiracetam is a novel antiepileptic drug with an unknown mechanism of action. To-date levetiracetam is not known to be associated with any clinically significant pharmacokinetic interaction. Similarly, levetiracetam has not been associated with any pharmacodynamic interactions. We present four patients with severe refractory epilepsy in whom introduction of levetiracetam led to disabling symptoms compatible with carbamazepine toxicity requiring either carbamazepine dose reduction or levetiracetam withdrawal. As carbamazepine and carbamazepine-epoxide blood levels were not altered during levetiracetam co-medication, a pharmacodynamic interaction is suggested. Therefore, during levetiracetam co-medication with carbamazepine, patients should be monitored closely for symptoms of carbamazepine toxicity.

Safety and tolerability of fexofenadine for the treatment of allergic rhinitis in children 2 to 5 years old.

PubMed

Milgrom, Henry; Kittner, Barbara; Lanier, Robert; Hampel, Frank C

2007-10-01

The safety of fexofenadine has been examined extensively in adults and school-age children. However, the safety of fexofenadine in children younger than 6 years has not been reported to date. To compare the safety and tolerability of twice-daily fexofenadine hydrochloride, 30 mg, and placebo in preschool children aged 2 to 5 years with allergic rhinitis. This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study, conducted between February 29, 2000, and June 14, 2001. Participants were randomized to either fexofenadine hydrochloride, 30 mg, or placebo twice daily for a 2-week period. To facilitate dosing, capsule content was mixed with applesauce (approximately 10 mL). Safety assessments depended on date of entry into the study because of an amendment to the protocol. Before the amendment, assessments included physical examination, vital signs reporting (oral temperature, heart rate, and respiratory rate), and adverse event (AE) reporting. After the amendment, safety assessments included laboratory testing (blood chemistry and hematology profiles), physical examination, 12-lead electrocardiography, and vital signs (oral temperature, blood pressure, heart rate, and respiratory rate) and AE reporting. Treatment-emergent AEs were observed in 116 of 231 participants receiving placebo and 111 of 222 receiving fexofenadine. These AEs were possibly related to study medication in 19 (8.2%) and 21 (9.5%) of the participants receiving placebo and fexofenadine, respectively, and most frequently involved the digestive system. No clinically relevant differences in laboratory measures, vital signs, and physical examinations were observed. The findings show that fexofenadine hydrochloride, 30 mg, is well tolerated and has a good safety profile in children aged 2 to 5 years with allergic rhinitis.

Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder.

PubMed

Ward, Kristen; Citrome, Leslie

2018-02-01

The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED). Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the clinical trials investigating the efficacy and safety of this medication for the management of BED. Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for the treatment of BED. It is an inactive prodrug of d-amphetamine that extends the half-life of d-amphetamine to allow for once daily dosing. D-amphetamine acts primarily to increase the concentrations of synaptic dopamine and norepinephrine. Metabolism of LDX to d-amphetamine occurs when peptidases in red blood cells cleave the covalent bond between d-amphetamine and l-lysine. D-amphetamine is then further metabolized by CYP2D6. Excretion is primarily through renal mechanisms. In clinical trials, LDX demonstrated statistical and clinical superiority over placebo in reducing binge eating days per week at doses of 50 and 70 mg daily. Commonly reported side effects of LDX include dry mouth, insomnia, weight loss, and headache, and its use should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia or coronary artery disease. As with all CNS stimulants, risk of abuse needs to be assessed prior to prescribing.

Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.

PubMed

Greenberg, Barry H; Chou, Willis; Saikali, Khalil G; Escandón, Rafael; Lee, Jacqueline H; Chen, Michael M; Treshkur, Tatyana; Megreladze, Irakli; Wasserman, Scott M; Eisenberg, Paul; Malik, Fady I; Wolff, Andrew A; Shaburishvili, Tamaz

2015-01-01

The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Lack of Effect of Vortioxetine on the Pharmacokinetics and Pharmacodynamics of Ethanol, Diazepam, and Lithium.

PubMed

Chen, Grace; Nomikos, George G; Affinito, John; Zhao, Zhen

2016-09-01

Because the multimodal antidepressant vortioxetine is likely to be coadministered with other central nervous system (CNS)-active drugs, potential drug-drug interactions warrant examination. These studies evaluated whether there are pharmacokinetic and/or pharmacodynamic interactions between vortioxetine and ethanol, diazepam, or lithium. This series of phase I studies included healthy men and women (only men in the lithium study) aged 18-45 years. The ethanol study was a randomized, double-blind, two-parallel group, four-period crossover study in which subjects received a single dose of vortioxetine (20 or 40 mg) or placebo with or without ethanol, and the diazepam study was a randomized, double-blind, placebo-controlled, two-sequence, two-period crossover study in which subjects received a single dose of diazepam following multiple doses of vortioxetine 10 mg/day or placebo. These two studies evaluated the effect of coadministration on standardized psychomotor parameters and on selected pharmacokinetic parameters of each drug. The lithium study was a single-blind, single-sequence study evaluating the effect of multiple doses of vortioxetine 10 mg/day on the steady-state pharmacokinetics of lithium. Concomitant administration of vortioxetine and single doses of either ethanol or diazepam had no significant effect on the psychomotor performance of subjects compared with administration of ethanol or diazepam alone. Vortioxetine had no significant effect on the pharmacokinetics of ethanol, diazepam, or lithium, and ethanol had no significant effect on the pharmacokinetics of vortioxetine. Concomitant administration of these agents with vortioxetine was generally well tolerated, with no clinically relevant drug-drug pharmacokinetic or pharmacodynamic interactions identified.

Ethnic or racial differences revisited: impact of dosage regimen and dosage form on pharmacokinetics and pharmacodynamics.

PubMed

Chen, Mei-Ling

2006-01-01

Ethnic or racial differences in pharmacokinetics and pharmacodynamics have been attributed to the distinctions in the genetic, physiological and pathological factors between ethnic/racial groups. These pharmacokinetic/pharmacodynamic differences are also known to be influenced by several extrinsic factors such as socioeconomic background, culture, diet and environment. However, it is noted that other factors related to dosage regimen and dosage form have largely been ignored or overlooked when conducting or analysing pharmacokinetic/pharmacodynamic studies in relation to ethnicity/race. Potential interactions can arise between the characteristics of ethnicity/race and a unique feature of dosage regimen or dosage form used in the study, which may partly account for the observed pharmacokinetic/pharmacodynamic differences between ethnic/racial groups. Ethnic/racial differences in pharmacokinetics/pharmacodynamics can occur from drug administration through a specific route that imparts distinct pattern of absorption, distribution, transport, metabolism or excretion. For example, racial differences in the first-pass metabolism of a drug following oral administration may not be relevant when the drug is applied to the skin. On the other hand, ethnic/racial difference in pharmacokinetics/pharmacodynamics can also happen via two different routes of drug delivery, with varying levels of dissimilarity between routes. For example, greater ethnic/racial differences were observed in oral clearance than in systemic clearance of some drugs, which might be explained by the pre-systemic factors involved in the oral administration as opposed to the intravenous administration. Similarly, changes in the dose frequency and/or duration may have profound impact on the ethnic/racial differences in pharmacokinetic/pharmacodynamic outcome. Saturation of enzymes, transporters or receptors at high drug concentrations is a possible reason for many observed ethnic/racial discrepancies between

Cyclosporine-inhibitable Cerebral Drug Transport Does not Influence Clinical Methadone Pharmacodynamics

PubMed Central

Meissner, Konrad; Blood, Jane; Francis, Amber M.; Yermolenka, Viktar; Kharasch, Evan D.

2015-01-01

Background Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans. Methods Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 hr). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures). Results Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis, or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4 ± 0.4 and 1.3 ± 0.5 mm/mg, respectively) and IV methadone (3.1 ± 1.0 and 3.2 ± 0.8 mm respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain. Conclusions Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution. PMID:25072223

Key interindividual determinants in MDMA pharmacodynamics.

PubMed

Papaseit, E; Torrens, M; Pérez-Mañá, C; Muga, R; Farré, M

2018-02-01

MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.

Pharmacokinetics and pharmacodynamics study of rhein treating renal fibrosis based on metabonomics approach.

PubMed

Sun, Hao; Luo, Guangwen; Xiang, Zheng; Cai, Xiaojun; Chen, Dahui

2016-12-01

The selection of effect indicators in the pharmacokinetic/ pharmacodynamic study of complex diseases to describe the relationship between plasma concentration and effect indicators is difficult. Three effect indicators of renal fibrosis were successfully determined. The relationship between pharmacokinetics and pharmacodynamics of rhein in rhubarb was elucidated. The study was a metabolomics analysis of rat plasma and pharmacokinetics/ pharmacodynamics of rhein. A sensitive and simple ultra performance liquid chromatography-tandem triple quadrupole mass spectrometry (UPLC-MS/MS) method was applied to determine the rhein plasma concentration in the rat model of renal fibrosis and rat sham-operated group after the administration of rhubarb decoction. Then, the ultra performance liquid chromatography-Micromass quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS) metabolomics method was used to screen biomarkers of renal fibrosis in rat plasma. Furthermore, the relationship between the plasma concentration of rhein and the concentration of three biomarkers directly related to renal fibrosis were analyzed. The three screened biomarkers could represent the effect of rhein treatment on renal fibrosis. Increasing the plasma concentration of rhein tended to restore the concentration of the three biomarkers in the model group compared with that in the sham-operated group. Evident differences in the area under the plasma concentration-time curve (AUC) of rhein were also observed under different pathological states. The results provide valuable information for the clinical application of rhubarb. Rhein intervention could recover the physiological balance in living organisms from the pharmacokinetic/pharmacodynamic levels. New information on the pharmacokinetic/pharmacodynamic study of complex diseases is provided. Copyright © 2016 Elsevier GmbH. All rights reserved.

Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Single- and multiple-dose Once-daily Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Chinese Patients With Type 2 Diabetes Mellitus.

PubMed

Zhao, Xia; Cui, Yimin; Zhao, Shuai; Lang, Benjamin; Broedl, Uli C; Salsali, Afshin; Pinnetti, Sabine; Macha, Sreeraj

2015-07-01

The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties and tolerability of the oral once-daily sodium glucose cotransporter 2 inhibitor empagliflozin, given in single and multiple 10 and 25 mg doses in Chinese patients with type 2 diabetes mellitus (T2DM). In a double-blind, placebo-controlled, parallel-group study, Chinese patients with T2DM were randomly assigned to receive a single dose of empagliflozin 10 or 25 mg or placebo on day 1 and once daily on days 3 to 9. A total of 24 patients were enrolled (14 men, 10 women; median age, 53.5 years; empagliflozin 10 mg, n = 9; empagliflozin 25 mg, n = 9; and placebo, n = 6). After both single- and multiple-dose administration, empagliflozin 10 and 25 mg were rapidly absorbed, reaching peak plasma concentrations within 1 to 1.5 hours (median), with plasma levels declining biphasically. Empagliflozin exposure increased roughly dose proportionally between 10 and 25 mg. Mean terminal elimination half-life values at steady state were 13.9 and 12.1 hours with empagliflozin 10 and 25 mg, respectively. Mean (SD) changes from baseline in 24-hour urinary glucose excretion (UGE) on day 1 were +87.7 (22.9) and +82.8 (18.8) g with empagliflozin 10 and 25 mg, respectively, compared with -1.0 (2.8) g with placebo, and on day 9 were +95.8 (24.1), +82.6 (34.8) g with empagliflozin 10 and 25 mg, respectively, compared with -4.1 (6.4) g with placebo. Mean (SD) changes from baseline in fasting plasma glucose (FPG) on day 2 were -18.7 (17.2) mg/dL and -25.8 (19.6) mg/dL with empagliflozin 10 and 25 mg, respectively, compared with -4.2 (15.2) mg/dL with placebo, and on day 9, were -25.6 (20.7) mg/dL and -31.4 (26.9) mg/dL with empagliflozin 10 and 25 mg, respectively, compared to -3.7 (7.5) mg/dL with placebo. On day 10, mean changes in weight were -1.1, -1.6, and +0.5 kg with empagliflozin 10 and 25 mg and placebo, respectively. Overall, empagliflozin 10 and 25 mg had safety profiles similar to that of

[Cannabinoids in palliative care: Systematic review and meta-analysis of efficacy, tolerability and safety].

PubMed

Mücke, M; Carter, C; Cuhls, H; Prüß, M; Radbruch, L; Häuser, W

2016-02-01

Cannabinoids have multiple medical indications in palliative care, such as relief of pain or nausea or increase of appetite and weight stabilisation. The value of cannabinoids for these indications is not resolved sufficiently for palliative patients. A systematic review with meta-analysis of the efficacy, tolerability and safety on the basis of randomised controlled studies (RCT) or randomised open label or crossover studies has not yet been conducted. An extensive search for RCTs, randomised open label or crossover studies dealing with the underlying question was performed in the databases of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, PubMed, Scopus and Clinicaltrials.gov up to April 2015. Studies with a duration of ≥ 2 weeks and ≥ 10 participants per treatment group were included into analysis. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables and risk differences (RD) for dichotomous variables were calculated. Out of initially 108 studies 9, with a total of 1561 participants suffering from advanced or end stage diseases, were included. The median study duration of the cancer research was 8 weeks (16 days-11 weeks), of the HIV research 6 weeks (3-12 weeks) and of the study concentrating on Alzheimer's 2 × 6 weeks. The outcome results for cannabis/cannabinoids vs. placebo in patients with cancer were not significant for the 30 % decrease in pain (RD: 0.07; 95 % confidence interval (CI): - 0.01 to 0.16; p = 0.07), caloric intake (SMD: 0.2; 95 % CI: - 0.66 to 1.06; p = 0.65) or sleep problems (SMD: - 0.09; 95 % CI: - 0.62 to 0.43; p = 0.72). In the treatment of HIV cannabinoids were superior to placebo for the outcome of weight change (SMD: 0.57; 95 % CI: 0.22-0.92; p = 0.001). Change in appetite was significant for the treatment of HIV (SMD: 0.57; 95 % CI: 0.11-1.03; p = 0.02), but

Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation.

PubMed

Richardson, A; Sakariassen, K S; Meyer, J-P; Alberts, P; Sorensen, A S

2013-03-01

This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes.. This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo. Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated. Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.

Safety and tolerability of the Easy Vax™ clinical epidermal electroporation system in healthy adults.

PubMed

El-Kamary, Samer S; Billington, Melissa; Deitz, Stephen; Colby, Elaina; Rhinehart, Howard; Wu, Yukun; Blackwelder, William; Edelman, Robert; Lee, Albert; King, Alan

2012-01-01

DNA vaccines are cost-effective and versatile, though intracellular delivery has been challenging in humans. Alternative delivery modalities such as electroporation have demonstrated improved immune responses, but are painful. In this single-center, double-blind, medical device trial, we evaluated the safety and tolerability of Easy Vax™ dermal electroporation system, alone (without DNA) in healthy adults. Three randomized protocol doses were administered to 10 subjects (80% white, 60% female, mean age: 32.1 years) in each of two areas (total of six doses). Two subjects complained of shooting pain, burning and/or tingling when doses were administered to the forearm region, but not the lateral deltoid regions. Subsequent doses for the remaining eight subjects were restricted to the deltoid regions only. Tolerability pain scores never exceeded 3 of 10 in the 11-Point Pain Rating scale, and 12 of 100 in the Visual Analog Scale (VAS), and lower in follow-up evaluations (P < 0.0001), with no significant difference between the three dosing protocols. Electrical properties of the skin, measured automatically by the device, showed no correlation between pain intensity and skin conductance. In conclusion, the Easy Vax™ electroporation device is safe and well tolerated when administered over the lateral deltoid skin regions in healthy volunteers.

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects.

PubMed

Jung, Jin Ah; Lee, Soo-Yun; Kim, Jung-Ryul; Ko, Jae-Wook; Jang, Seong Bok; Nam, Su Youn; Huh, Wooseong

2015-01-01

Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment. For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873-0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632-0.9701) for area under the concentration-time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946-1.0884) and 1.0072 (0.8893-1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events. The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their

Scaling Pharmacodynamics from In Vitro and Preclinical Animal Studies to Humans

PubMed Central

Mager, Donald E.; Woo, Sukyung; Jusko, William J.

2013-01-01

Summary An important feature of mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) models is the identification of drug- and system-specific factors that determine the intensity and time-course of pharmacological effects. This provides an opportunity to integrate information obtained from in vitro bioassays and preclinical pharmacological studies in animals to anticipate the clinical and adverse responses to drugs in humans. The fact that contemporary PK/PD modeling continues to evolve and seeks to emulate systems level properties should provide enhanced capabilities to scale-up pharmacodynamic data. Critical steps in drug discovery and development, such as lead compound and first in human dose selection, may become more efficient with the implementation and further refinement of translational PK/PD modeling. In this review, we highlight fundamental principles in pharmacodynamics and the basic expectations for in vitro bioassays and traditional allometric scaling in PK/PD modeling. Discussion of PK/PD modeling efforts for recombinant human erythropoietin is also included as a case study showing the potential for advanced systems analysis to facilitate extrapolations and improve understanding of inter-species differences in drug responses. PMID:19252333

Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers

PubMed Central

Lee, Jieon; Lee, Howard; Jang, Kyungho; Lim, Kyoung Soo; Shin, Dongseong; Yu, Kyung-Sang

2014-01-01

Purpose Although cilnidipine and valsartan are widely coadministered to patients with hypertension, their drug–drug interaction potential has not been investigated. This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of cilnidipine and valsartan, both alone and in combination, in healthy male subjects. Patients and methods Fifty-four subjects, enrolled into an open-label, single-dose, three-treatment, three-period crossover study, randomly received cilnidipine (10 mg), valsartan (160 mg), or both according to one of six sequences. Blood samples were collected at baseline and up to 24 hours after drug administration in each period. Plasma concentrations of cilnidipine and valsartan were determined by liquid chromatography with tandem mass spectrometry. Maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to the last measurable time (AUClast) were estimated using a noncompartmental method. Tolerability was evaluated by assessing adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory tests. Blood pressure was also measured for PD assessment. Results A total of 51 subjects completed the study. The PK profile of cilnidipine was not significantly affected by coadministered valsartan; the geometric mean ratio and 90% confidence interval (90% CI) of AUClast for cilnidipine with and without valsartan was 1.04 (0.98–1.10). Likewise, cilnidipine did not affect the PK of valsartan; the geometric mean ratio (90% CI) of AUClast for valsartan with and without cilnidipine was 0.94 (0.83–1.07). Coadministration of cilnidipine and valsartan reduced blood pressure in an additive way. No serious AEs were reported, and both cilnidipine and valsartan were well tolerated. Conclusion Coadministered cilnidipine and valsartan do not cause a significant PK or PD interaction, and they are well tolerated. PMID:25336921

Elucidating pharmacodynamic interaction of silver nanoparticle - topical deliverable antibiotics.

PubMed

Thirumurugan, G; Seshagiri Rao, J V L N; Dhanaraju, M D

2016-07-18

In order to exploit the potential benefits of antimicrobial combination therapy, we need a better understanding of the circumstances under which pharmacodynamic interactions expected. In this study, Pharmacodynamic interactions between silver nanoparticle (SNP) and topical antibiotics such as Cefazolin (CEF), Mupirocin (MUP), Gentamycin (GEN), Neomycin (NEO), Tetracycline (TET), Vancomycin (VAN) were investigated using the MIC test, Combination assay followed by Fractional Inhibitory concentration Index and Agar well diffusion method. SNP + MUP, SNP + NEO, SNP + VAN combinations showed Synergism (SN) and SNP + CEF, SNP + GEN, SNP + TET showed Partial synergism (PS) against Staphylococcus aureus. Four combinations (SNP + CEF, SNP + MUP, SNP + GEN, SNP + VAN) showed SN, SNP + TET showed PS and Indifferent effect (ID) were observed for SNP + NEO against Pseudomonas aeruginosa. SN was observed for SNP + CEF, SNP + GEN, SNP + NEO, SNP + TET and SNP + MUP showed ID, SNP + VAN showed PS against Escherichia coli. In addition, we elucidated the possible mechanism involved in the pharmacodynamic interaction between SNP-topical antibiotics by increased ROS level, membrane damage following protein release, K(+) leakage and biofilm inhibition. Thus, our findings support that conjugation of the SNP with topical antibiotics have great potential in the topical formulation when treating complex resistant bacterial infections and where there is a need of more concentration to kill pathogenic bacteria.

Elucidating pharmacodynamic interaction of silver nanoparticle - topical deliverable antibiotics

NASA Astrophysics Data System (ADS)

Thirumurugan, G.; Seshagiri Rao, J. V. L. N.; Dhanaraju, M. D.

2016-07-01

In order to exploit the potential benefits of antimicrobial combination therapy, we need a better understanding of the circumstances under which pharmacodynamic interactions expected. In this study, Pharmacodynamic interactions between silver nanoparticle (SNP) and topical antibiotics such as Cefazolin (CEF), Mupirocin (MUP), Gentamycin (GEN), Neomycin (NEO), Tetracycline (TET), Vancomycin (VAN) were investigated using the MIC test, Combination assay followed by Fractional Inhibitory concentration Index and Agar well diffusion method. SNP + MUP, SNP + NEO, SNP + VAN combinations showed Synergism (SN) and SNP + CEF, SNP + GEN, SNP + TET showed Partial synergism (PS) against Staphylococcus aureus. Four combinations (SNP + CEF, SNP + MUP, SNP + GEN, SNP + VAN) showed SN, SNP + TET showed PS and Indifferent effect (ID) were observed for SNP + NEO against Pseudomonas aeruginosa. SN was observed for SNP + CEF, SNP + GEN, SNP + NEO, SNP + TET and SNP + MUP showed ID, SNP + VAN showed PS against Escherichia coli. In addition, we elucidated the possible mechanism involved in the pharmacodynamic interaction between SNP-topical antibiotics by increased ROS level, membrane damage following protein release, K+ leakage and biofilm inhibition. Thus, our findings support that conjugation of the SNP with topical antibiotics have great potential in the topical formulation when treating complex resistant bacterial infections and where there is a need of more concentration to kill pathogenic bacteria.

The slowpoke gene is necessary for rapid ethanol tolerance in Drosophila.

PubMed

Cowmeadow, R B; Krishnan, H R; Atkinson, N S

2005-10-01

Ethanol is one of the most commonly used drugs in the world. We are interested in the compensatory mechanisms used by the nervous system to counter the effects of ethanol intoxication. Recently, the slowpoke BK-type calcium-activated potassium channel gene has been shown to be involved in ethanol sensitivity in Caenorhabditis elegans and in rapid tolerance to the anesthetic benzyl alcohol in Drosophila. We used Drosophila mutants to investigate the role of slowpoke in rapid tolerance to sedation with ethanol vapor. Rapid tolerance was defined as a reduction in the sedative phase caused by a single previous sedation. The ethanol and water contents of flies were measured to determine if pharmacodynamic changes could account for tolerance. A saturated ethanol air stream caused sedation in <20 min and resulted in rapid tolerance that was apparent 4 hr after sedation. Two independently isolated null mutations in the slowpoke gene eliminated the capacity for tolerance. In addition, a third mutation that blocked expression specifically in the nervous system also blocked rapid tolerance. Water measurements showed that both ethanol and mock sedation caused equivalent dehydration. Furthermore, a single prior exposure to ethanol did not cause a change in the ethanol clearance rate. Rapid tolerance, measured as a reduction in the duration of sedation, is a pharmacokinetic response to ethanol that does not occur without slowpoke expression in the nervous system in Drosophila. The slowpoke channel must be involved in triggering or producing a homeostatic mechanism that opposes the sedative effects of ethanol.

A Phase I and pharmacodynamic study of AT9283, a small molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis

PubMed Central

Foran, James; Ravandi, Farhad; Wierda, William; Garcia-Manero, Guillermo; Verstovsek, Srdan; Kadia, Tapan; Burger, Jan; Yule, Murray; Langford, Gillian; Lyons, John; Ayrton, John; Lock, Victoria; Borthakur, Gautham; Cortes, Jorge; Kantarjian, Hagop

2014-01-01

Purpose To identify the MTD of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics and preliminary evidence of efficacy. Patients and Methods AT9283 was administered as a continuous 72h infusion every 21 days. Doses were escalated by a standard 3+3 design. After the MTD for the 72h infusion was identified, infusion duration was increased incrementally to 96h and 120h. In total, 48 patients received ≥1 cycle of AT9283. Median age was 61 years (range 22–86 years), with 56% men, 75% diagnosed with AML, and 89% having received ≥3 (up to 16) prior lines of therapy. Results 324 mg/m2/72h AT9283 was determined to be the MTD. DLTs were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leucopenia and mucositis. Bone marrow blasts decreased ≥38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of aurora kinase B inhibition. Two patients with accelerated phase CML showed evidence of benefit, manifest as a cytogenetic response in one case; one patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional. Conclusion AT9283 tolerability was strongly dose dependent with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations. PMID:24355079

Safety and tolerability of BufferGel, a novel vaginal microbicide, in women in the United States.

PubMed

Mayer, K H; Peipert, J; Fleming, T; Fullem, A; Moench, T; Cu-Uvin, S; Bentley, M; Chesney, M; Rosenberg, Z

2001-02-01

BufferGel (ReProtect, LLC) is a vaginal gel with an acidic buffering action that was designed to prevent vaginal neutralization by semen. The purpose of this study was to evaluate the safety and tolerability of BufferGel (ReProtect, Limited Liability Company) applied vaginally either once or twice daily by 27 women who were at low risk for acquisition of human immunodeficiency virus (HIV). Participants initially used the product once daily for 14 days and then twice daily for 14 days; they underwent colposcopy before and after product exposure. BufferGel was well tolerated, although two-thirds of the participants reported at least 1 mild or moderate adverse experience. The most common adverse events were irritative genitourinary symptoms. Product use was discontinued after 3 adverse events. BufferGel was well tolerated in women at low risk for acquisition of HIV; toxicity was limited and occurred at frequencies similar to those in women who did not use any vaginal product and at levels lower than in women who used detergent-based microbicides.

Safety and Tolerability of Hyperbaric Oxygen Therapy in Cats and Dogs.

PubMed

Birnie, Gemma L; Fry, Darren R; Best, Matthew P

2018-05-14

This prospective clinical trial was designed to evaluate the safety of hyperbaric oxygen therapy (HBOT) in a population of cats and dogs with a variety of naturally occurring diseases. Seventy-eight dogs and twelve cats with various naturally occurring disease conditions, who had the potential to benefit from HBOT, were enrolled in the study. These patients were treated with HBOT in a monoplace hyperbaric oxygen chamber at 2 air pressure absolute for a treatment length of either 45 min or 60 min. There were 230 hyperbaric oxygen treatments performed during the study period. No major adverse effects were observed. There were 76 minor adverse effects recorded, which were not considered to be of clinical significance. Hyperbaric oxygen therapy was well tolerated and there were no major adverse effects recorded during treatment.

Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.

PubMed

Kukanich, Butch; Borum, Stacy L

2008-05-01

To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. 6 healthy Greyhounds, 3 male and 3 female. Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.

Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

PubMed

Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

2016-01-01

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

Hollow Fiber Methodology for Pharmacokinetic/Pharmacodynamic Studies of Antimalarial Compounds

PubMed Central

Caton, Emily; Nenortas, Elizabeth; Bakshi, Rahul P.; Shapiro, Theresa A.

2016-01-01

Knowledge of pharmacokinetic/pharmacodynamic (PK/PD) relationships can enhance the speed and economy of drug development by enabling informed and rational decisions at every step, from lead selection to clinical dosing. For anti-infective agents in particular, dynamic in vitro hollow fiber cartridge experiments permit exquisite control of kinetic parameters and the study of their consequent impact on pharmacodynamic efficacy. Such information is of great interest for the cost-restricted but much-needed development of new antimalarial drugs, especially since major human pathogen Plasmodium falciparum can be cultivated in vitro but is not readily available in animal models. This protocol describes the materials and procedures for determining the PK/PD relationships of antimalarial compounds. PMID:26995353

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers

PubMed Central

Yap, Timothy A.; Yan, Li; Patnaik, Amita; Tunariu, Nina; Biondo, Andrea; Fearen, Ivy; Papadopoulos, Kyriakos P.; Olmos, David; Baird, Richard; Delgado, Liliana; Tetteh, Ernestina; Beckman, Robert A.; Lupinacci, Lisa; Riisnaes, Ruth; Decordova, Shaun; Heaton, Simon P.; Swales, Karen; deSouza, Nandita M; Leach, Martin O.; Garrett, Michelle D.; Sullivan, Daniel M.; de Bono, Johann S.; Tolcher, Anthony W.

2014-01-01

Purpose Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60mg on alternate days (QOD). Due to a long half-life (60-80h), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Experimental Design Patients with advanced cancers were enrolled onto a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers, and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy and intrinsic susceptibility-weighted MRI. Results Seventy-one patients were enrolled; 38 patients had 60mg MK-2206 QOD, while 33 received MK-2206 at 90mg, 135mg, 150mg, 200mg, 250mg, and 300mg QW. The QW MK-2206 MTD was established at 200mg following dose-limiting rash at 250mg and 300mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially-obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Conclusions MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200mg QW is currently used in phase II MK-2206 monotherapy and combination studies. PMID:25239610

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PubMed

Yap, Timothy A; Yan, Li; Patnaik, Amita; Tunariu, Nina; Biondo, Andrea; Fearen, Ivy; Papadopoulos, Kyriakos P; Olmos, David; Baird, Richard; Delgado, Liliana; Tetteh, Ernestina; Beckman, Robert A; Lupinacci, Lisa; Riisnaes, Ruth; Decordova, Shaun; Heaton, Simon P; Swales, Karen; deSouza, Nandita M; Leach, Martin O; Garrett, Michelle D; Sullivan, Daniel M; de Bono, Johann S; Tolcher, Anthony W

2014-11-15

Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). ©2014 American Association for Cancer Research.

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.

PubMed

Wensing, Georg; Haase, Claus; Brendel, Erich; Böttcher, Michael Friedrich

2007-12-01

BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study. 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h. Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h. Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.

Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions

PubMed Central

Ben-Eltriki, Mohamed; Deb, Subrata; Guns, Emma S. Tomlinson

2016-01-01

Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy. PMID:26918053

Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study.

PubMed

Olde Rikkert, Marcel G M; Verhey, Frans R; Blesa, Rafael; von Arnim, Christine A F; Bongers, Anke; Harrison, John; Sijben, John; Scarpini, Elio; Vandewoude, Maurits F J; Vellas, Bruno; Witkamp, Renger; Kamphuis, Patrick J G H; Scheltens, Philip

2015-01-01

The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.

The hollow fibre assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells

PubMed Central

Temmink, O H; Prins, H-J; van Gelderop, E; Peters, G J

2006-01-01

The Hollow Fibre Assay (HFA) is usually applied as an early in vivo model for anti-cancer drug screening, but is potentially an excellent model for short-term in vivo pharmacodynamic studies. We used the model to study the in vivo role of thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) in the cytotoxicity and pharmacodynamics of TAS-102 in colon cancer cells. TAS-102 is a new oral drug formulation, which is composed of trifluorothymidine (TFT) and thymidine phosphorylase inhibitor (TPI), which prevents TFT degradation. We compared the activity with Xeloda (capecitabine), which is activated by TP into 5FU. Hollow fibres filled with human Colo320 or Colo320TP1 colorectal cancer cells with deficient or high TP expression, respectively, were implanted subcutaneously (s.c.) at both flanks of BALB/c mice. The mice were treated orally over 5 days with TAS-102, TFT alone, 5′DFUR±TPI or capecitabine at their maximum tolerated dose (MTD). The cells were retrieved from the fibres and assayed for growth (MTT assay), cell cycle distribution (flow cytometry) and apoptosis induction (FragEL method). TAS-102 induced considerable growth inhibition (50%, P<0.01) to both cell lines, which was completely abolished in the absence of TPI. Capecitabine and its metabolite 5′DFUR reduced proliferation of Colo320TP1 cells in the fibres significantly (down to 25–40%), but much less in Colo320 cells, whereas addition of TPI reduced the effect of 5′DFUR, although not completely. These differences in cytotoxic effects were reflected in the pharmacodynamic evaluation. TAS-102 induced a G2M-phase arrest (from 25 to 40%) and apoptosis (>8-fold), which was more pronounced in Colo320 than in Colo320TP1. Again, omission of TPI neutralised the effect of TAS-102. Similarly, 5′DFUR and capecitabine induced a significant G2M-phase arrest (up to 45%) in the Colo320TP1 cell line, but less pronounced in the parental Colo320. Addition of TPI to 5′DFUR reduced

Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

PubMed

Brown, Jacob T; Bishop, Jeffrey R

2015-01-01

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

Pharmacokinetics, Safety, and Tolerability of Lamotrigine Chewable/Dispersible Tablet Following Repeat-Dose Administration in Healthy Chinese Volunteers.

PubMed

Li, Yan; Zhang, Fan; Xu, Yanmei; Hu, Joice; Li, Huafang

2018-03-26

In this open-label, single-center study, the pharmacokinetics, safety, and tolerability of lamotrigine chewable/dispersible tablets were assessed in healthy Chinese volunteers. Each volunteer (N = 16) received repeat doses of oral lamotrigine titrated from 25 mg to 50 mg to 100 mg over 42 days and was followed up for 10-17 days. Safety and tolerability were assessed throughout the study. Lamotrigine pharmacokinetic parameters were estimated using noncompartmental analysis. Overall, 15 (94%) volunteers completed the study. Lamotrigine serum concentrations peaked 2.5 hours postdose, with a mean terminal half-life of 36.8 hours. The apparent lamotrigine oral clearance was 1577.88 mL/h. The accumulation ratios (day 14 vs day 1) were 2.53 and 2.58 for area under the curve and peak concentration, respectively. Lamotrigine 25 to 100 mg once daily exhibited dose-proportional pharmacokinetics (based on area under the curve and peak concentration), following repeat dosing. Nine volunteers reported adverse events, 2 experienced oropharyngeal pain, each receiving 25 mg and 50 mg. One volunteer withdrew due to an increase in liver enzymes. No deaths, serious adverse effects, or skin rashes were reported during the study. No new safety concerns were observed. Overall, the pharmacokinetic profiles after repeat doses of lamotrigine chewable/dispersible tablets once daily in a Chinese population were similar to those observed in Western populations. © 2018, The American College of Clinical Pharmacology.

Application of Pharmacokinetics and Pharmacodynamics in Product Life Cycle Management. A Case Study with a Carbidopa-Levodopa Extended-Release Formulation.

PubMed

Modi, Nishit B

2017-05-01

Increasing costs in discovering and developing new molecular entities and the continuing debate on limited company pipelines mean that pharmaceutical companies are under significant pressure to maximize the value of approved products. Life cycle management in the context of drug development comprises activities to maximize the effective life of a product. Life cycle approaches can involve new formulations, new routes of delivery, new indications or expansion of the population for whom the product is indicated, or development of combination products. Life cycle management may provide an opportunity to improve upon the current product through enhanced efficacy or reduced side effects and could expand the therapeutic market for the product. Successful life cycle management may include the potential for superior efficacy, improved tolerability, or a better prescriber or patient acceptance. Unlike generic products where bioequivalence to an innovator product may be sufficient for drug approval, life cycle management typically requires a series of studies to characterize the value of the product. This review summarizes key considerations in identifying product candidates that may be suitable for life cycle management and discusses the application of pharmacokinetics and pharmacodynamics in developing new products using a life cycle management approach. Examples and a case study to illustrate how pharmacokinetics and pharmacodynamics contributed to the selection of dosing regimens, demonstration of an improved therapeutic effect, or regulatory approval of an improved product label are presented.

Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans.

PubMed

Evans, Erica K; Tester, Richland; Aslanian, Sharon; Karp, Russell; Sheets, Michael; Labenski, Matthew T; Witowski, Steven R; Lounsbury, Heather; Chaturvedi, Prasoon; Mazdiyasni, Hormoz; Zhu, Zhendong; Nacht, Mariana; Freed, Martin I; Petter, Russell C; Dubrovskiy, Alex; Singh, Juswinder; Westlin, William F

2013-08-01

Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.

Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability.

PubMed

Bigaeva, Emilia; Doorn, Eva van; Liu, Heng; Hak, Eelko

2016-01-01

QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials. A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality. Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04-6.24). No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10-15.35 and RR 2.55, 95% CI 1.41-4.59, respectively). ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08-10.97). Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. This meta-analysis is limited by the relatively

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical

Pharmacokinetics and pharmacodynamics of the proton pump inhibitors.

PubMed

Shin, Jai Moo; Kim, Nayoung

2013-01-01

Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H(+), K(+)-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.

Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.

PubMed

Yeo, Astrid; Li, Li; Warren, Liling; Aponte, Jennifer; Fraser, Dana; King, Karen; Johansson, Kelley; Barnes, Allison; MacPhee, Colin; Davies, Richard; Chissoe, Stephanie; Tarka, Elizabeth; O'Donoghue, Michelle L; White, Harvey D; Wallentin, Lars; Waterworth, Dawn

2017-01-01

Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS

Feasibility, tolerability and safety of pediatric hyperpolarized 129Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis.

PubMed

Walkup, Laura L; Thomen, Robert P; Akinyi, Teckla G; Watters, Erin; Ruppert, Kai; Clancy, John P; Woods, Jason C; Cleveland, Zackary I

2016-11-01

Hyperpolarized 129 Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. To assess the feasibility, safety and tolerability of hyperpolarized 129 Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent 129 Xe MRI, receiving up to three doses of 129 Xe gas prepared by either a commercially available or a homebuilt 129 Xe polarizer. Subject heart rate and SpO 2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. All children tolerated multiple doses of 129 Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO 2 (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO 2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following 129 Xe MRI, but all were deemed unrelated to the study. The feasibility, safety and tolerability of 129 Xe MRI has been assessed in a small group of children as young as 6 years. SpO 2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were

Principles of Safety Pharmacology

PubMed Central

Pugsley, M K; Authier, S; Curtis, M J

2008-01-01

Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring. This article sets out to explain the drivers for Safety Pharmacology so that the wider pharmacology community is better placed to understand the discipline. It concludes with a summary of principles that may help inform future resolution of unmet needs (especially establishing model validation for accurate risk assessment). Subsequent articles in this issue of the journal address specific aspects of Safety Pharmacology to explore the issues of model choice, the burden of proof and to highlight areas of intensive activity (such as testing for drug-induced rare event liability, and the challenge of testing the safety of so-called biologics (antibodies, gene therapy and so on.). PMID:18604233

Assessment of the pharmacodynamics of intranasal, intravenous and oral scopolamine

NASA Technical Reports Server (NTRS)

Tietze, Karen J.

1990-01-01

Space motion sickness is an important issue in the space medical sciences program. One of the objectives of the ongoing clinical experimental protocol Pharmacokinetics of Intranasal Scopolamine in Normal Subjects is to evaluate the pharmacodynamics of scopolamine using salivary flow rate and pH profiles and cognitive performance tests as pharmacodynamic parameters. Normal volunteers collected saliva and performed the NTI Multiresource Performance Battery tests at designed time intervals to establish control saliva flow rates, salivary pH profiles, and the characteristics of the learning curve for the performance program under normal conditions. In the clinical part of the study, saliva samples and performance test scores are collected from healthy nonsmoking subjects after receiving a single 0.4 mg dose of either intranasal, intravenous, or oral scopolamine.

Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trifilieff, Alexandre; Ethell, Brian T.; Sykes, David A.

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1more » or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates

A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State.

PubMed

Chen, Chun Lin; Desai-Krieger, Daksha; Ortiz, Stephan; Kerolous, Majid; Wright, Harold M; Ghahramani, Parviz

2015-01-01

Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol-valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol-valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol-valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms.

The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination with Febuxostat When Treating Hyperuricemia Associated with Gout.

PubMed

Steinberg, Alexandra S; Vince, Bradley D; Choi, Yun-Jung; Martin, Robert L; McWherter, Charles A; Boudes, Pol F

2017-03-01

Arhalofenate (ARH), in development for gout, has uricosuric and anti-flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety. Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2. Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC) (0-t) of ARH acid + FBX/ARH acid was 108%. The AUC (0-t) of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe. ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe. NCT02252835.

Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer.

PubMed

Maughan, Benjamin L; Suzman, Daniel L; Luber, Brandon; Wang, Hao; Glavaris, Stephanie; Hughes, Robert; Sullivan, Rana; Harb, Rana; Boudadi, Karim; Paller, Channing; Eisenberger, Mario; Demarzo, Angelo; Ross, Ashely; Antonarakis, Emmanuel S

2016-12-01

Hedgehog (Hh) pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state. We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer (mCRPC) would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients. This is a single-arm study of oral daily vismodegib in men with mCRPC. All patients were required to have biopsies of the tumor and skin (a surrogate tissue) at baseline and after 4 weeks of therapy. Ten patients were planned for enrollment. The primary outcome was the pharmacodynamic assessment of Gli1 mRNA suppression with vismodegib in tumor tissue. Secondary outcomes included PSA response rates, progression-free survival (PFS), overall survival (OS) and safety. Nine patients were enrolled. Gli1 mRNA was significantly suppressed by vismodegib in both tumor tissue (4/7 evaluable biopsies, 57%) and benign skin biopsies (6/8 evaluable biopsies, 75%). The median number of treatment cycles completed was three, with a median PFS of 1.9 months (95% CI 1.3, NA), and a median OS of 7.04 months (95% CI 3.4, NA). No patient achieved a PSA reduction or a measurable tumor response. Safety data were consistent with the known toxicities of vismodegib. Hh signaling, as measured by Gli1 mRNA expression in mCRPC tissues, was suppressed with vismodegib in the majority of patients. Despite this pharmacodynamic response that indicated target inhibition in some patients, there was no apparent signal of clinical activity. Vismodegib will not be developed further as monotherapy in mCRPC.

Interference of hawthorn on serum digoxin measurements by immunoassays and pharmacodynamic interaction with digoxin.

PubMed

Dasgupta, Amitava; Kidd, Laura; Poindexter, Brian J; Bick, Roger J

2010-08-01

Hawthorn is an herb indicated for treating cardiac illness. Because a patient taking digoxin may also take hawthorn, we investigated potential interference of hawthorn in serum digoxin measurements using immunoassays as well as pharmacodynamic interaction between hawthorn and digoxin. Hawthorn contains alkaloids that are structurally similar to digoxin and may interfere with serum digoxin measurement using immunoassays. In addition, hawthorn has cardioactive properties similar to digoxin. To study potential pharmacodynamic interaction between hawthorn and digoxin. The effects of hawthorn extract on serum digoxin measurements using Digoxin III (Abbott Laboratories, Abbott Park, Illinois) and the Tina-Quant digoxin assay (Roche Diagnostics, Indianapolis, Indiana) were investigated using 2 different brands of extract. To study the pharmacodynamic interaction between hawthorn and digoxin, we used an isolated adult rat cardiomyocyte system, measuring calcium transients by real-time fluorescence spectrophotometry. Hawthorn interfered only with the Digoxin III immunoassay but had no effect on the Tina-Quant assay. Both hawthorn extracts increased intracellular calcium levels, but the lack of additive response with digoxin suggests both may bind to the same site of Na, K adenosine triphosphatase. Because of interference of hawthorn with a digoxin immunoassay and pharmacodynamic interaction with digoxin, a patient receiving digoxin should avoid hawthorn.

Pharmacodynamics of temazepam in primary insomnia: assessment of the value of quantitative electroencephalography and saccadic eye movements in predicting improvement of sleep.

PubMed

Tuk, B; Oberyé, J J; Pieters, M S; Schoemaker, R C; Kemp, B; van Gerven, J; Danhof, M; Kamphuisen, H A; Cohen, A F; Breimer, D D; Peck, C C

1997-10-01

Quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect. The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated. The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters. In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.

Safety, tolerability, and immunogenicity of zoster vaccine in subjects on chronic/maintenance corticosteroids.

PubMed

Russell, Amy F; Parrino, Janie; Fisher, Chester L; Spieler, Wolfgang; Stek, Jon E; Coll, Kathleen E; Su, Shu-Chih; Xu, Jin; Li, Xiaoming; Schlienger, Katia; Silber, Jeffrey L

2015-06-17

This randomized, placebo-controlled study assessed the safety, tolerability, and immunogenicity of live virus zoster vaccine (ZV) in individuals receiving chronic/maintenance systemic corticosteroid therapy (daily dose equivalent of 5-20mg prednisone) for ≥2 weeks prior to vaccination and ≥6 weeks postvaccination. Subjects were followed for adverse experiences (AEs), exposure to varicella or herpes zoster (HZ), or development of varicella/varicella-like or HZ/HZ-like rashes for 42 days postvaccination (primary safety follow-up period) and for serious AEs (SAEs) through Day 182 postvaccination (secondary follow-up period). Varicella-zoster virus (VZV) antibody titers by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and at Week 6 postvaccination. The proportions of subjects reporting systemic AEs and SAEs were similar in both groups. A higher percentage of subjects reported injection-site AEs in the ZV group (21.5%) than in the placebo group (12.1%). One SAE of ophthalmic HZ (onset Day 16 postvaccination) was reported in the ZV group and deemed vaccine-related by the study investigator; however, PCR testing confirmed the presence of wild-type (not vaccine strain) VZV. Geometric mean titer (GMT) at 6 weeks postvaccination was higher for ZV recipients than placebo recipients, with estimated geometric mean fold rises (GMFR) of 2.3 (CI: 2.0, 2.7) and 1.1 (CI: 1.0, 1.2) respectfully. In adults ≥60 years old on chronic/maintenance corticosteroids, ZV was generally well tolerated and immunogenic. The VZV-specific gpELISA antibody GMT at 6 weeks postvaccination and the GMFR from baseline to 6 weeks postvaccination were higher in the ZV group than in the placebo group. Copyright © 2015 Elsevier Ltd. All rights reserved.

Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine

PubMed Central

Braun, Marina; Cawello, Willi; Boekens, Hilmar; Horstmann, Rolf

2009-01-01

AIMS To evaluate the influence of the antiemetic agent domperidone on steady-state pharmacokinetics, safety and tolerability of multiple-dose treatment of the transdermally applied non-ergolinic dopamine agonist rotigotine. METHODS Sixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two-way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h)−1, 10 cm2, total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed. RESULTS The primary steady-state pharmacokinetic parameters (Cmax,ss and AUC(0–24),ss) were similar with or without co-administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 0.96 (0.86, 1.08) and AUC(0–24),ss 0.97 (0.87, 1.08). tmax,ss, t1/2, secondary parameters calculated on days 4/5 after repeated patch application (Cmin,ss, Cave,ss, AUC(0–tz)) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side-effect nausea was seen with domperidone comedication. CONCLUSIONS No changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone. PMID:19094160

Evaluation of the Safety, Tolerability, and Pharmacokinetics of Gammaplex® 10% Versus Gammaplex® 5% in Subjects with Primary Immunodeficiency.

PubMed

Wasserman, Richard L; Melamed, Isaac R; Stein, Mark R; Jolles, Stephen; Norton, Miranda; Moy, James N

2017-04-01

This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs). Eligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only. The primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC 0-28 ) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%. In this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura.

New formulations of amoxicillin/clavulanic acid: a pharmacokinetic and pharmacodynamic review.

PubMed

Sánchez Navarro, Amparo

2005-01-01

The pharmacokinetic properties of amoxicillin and clavulanic acid when used alone or in combination are extensively reviewed and discussed in this article. The reported data support a nonlinear absorption process for amoxicillin. Saturable transport mechanisms, limited solubility and the existence of an absorption window are possibly involved in the gastrointestinal absorption of this antibacterial, all leading to a decrease in the peak plasma concentration (Cmax)/dose ratio, a prolongation of the time to reach Cmax, and broad variability for high doses of amoxicillin. Data available in the literature also suggest a possible interaction between amoxicillin and clavulanic acid that might decrease the absolute bioavailability of clavulanic acid. In the present review the intrinsic pharmacodynamics of each drug, together with the synergism produced by the amoxicillin/clavulanic acid association, are also reviewed and analysed. Not only beta-lactamase-producing strains, but also Streptococcus pneumoniae strains, seem to be more efficiently eradicated by the association of amoxicillin and clavulanic acid, and a relevant post-antibacterial effect and post-beta-lactamase inhibitor effect are likely to operate when amoxicillin is administered together with clavulanic acid. The principles of pharmacokinetic/pharmacodynamic analysis applied to amoxicillin are reviewed, with special emphasis being placed on the results obtained from in vitro studies and animal models regarding the new pharmacokinetically enhanced formulation. Theoretical considerations concerning the efficacy of this formulation provided by the application of pharmacokinetic/pharmacodynamic analysis to the scarce pharmacokinetic data available are also included. The broad pharmacokinetic variability of both amoxicillin and clavulanic acid, particularly when administered together and at high doses of amoxicillin, is highlighted and the interest in considering this aspect to improve predictions based on

Pharmacokinetic-pharmacodynamic modelling of the antihistaminic (H1) effect of bilastine.

PubMed

Jauregizar, Nerea; de la Fuente, Leire; Lucero, Maria Luisa; Sologuren, Ander; Leal, Nerea; Rodríguez, Mónica

2009-01-01

To model the pharmacokinetic and pharmacodynamic relationship of bilastine, a new histamine H(1) receptor antagonist, from single- and multiple-dose studies in healthy adult subjects. The pharmacokinetic model was developed from different single-dose and multiple-dose studies. In the single-dose studies, a total of 183 subjects received oral doses of bilastine 2.5, 5, 10, 20, 50, 100, 120, 160, 200 and 220 mg. In the multiple-dose studies, 127 healthy subjects received bilastine 10, 20, 40, 50, 80, 100, 140 or 200 mg/day as multiple doses during a 4-, 7- or 14-day period. The pharmacokinetic profile of bilastine was investigated using a simultaneous analysis of all concentration-time data by means of nonlinear mixed-effects modelling population pharmacokinetic software NONMEM version 6.1. Plasma concentrations were modelled according to a two-compartment open model with first-order absorption and elimination. For the pharmacodynamic analysis, the inhibitory effect of bilastine (inhibition of histamine-induced wheal and flare) was assessed on a preselected time schedule, and the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. An indirect response model was developed to describe the pharmacodynamic relationships between flare or wheal areas and bilastine plasma concentrations. Finally, once values of the concentration that produced 50% inhibition (IC(50)) had been estimated for wheal and flare effects, simulations were carried out to predict plasma concentrations for the doses of bilastine 5, 10 and 20 mg at steady state (72-96 hours). A non-compartmental analysis resulted in linear kinetics of bilastine in the dose range studied. Bilastine was characterized by two-compartmental kinetics with a rapid-absorption phase (first-order absorption rate constant = 1.50 h(-1)), plasma peak concentrations were observed at 1 hour following administration and the maximal response was observed at approximately 4 hours

First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

PubMed

Kletzl, H; Guenther, A; Höflich, A; Höflich, C; Frystyk, J; Staack, R F; Schick, E; Wandel, C; Bleich, N; Metzger, F

2017-04-01

This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50μg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bioavailability and Pharmacodynamics of Promethazine in Human Subjects

NASA Technical Reports Server (NTRS)

Putcha, Lakshmi; Flynn, Chris; Paloski, W. H. (Technical Monitor)

2000-01-01

Space Motion Sickness (SMS) is often treated in space with promethazine (PMZ). Anecdotal reports indicate that the common side effects of drowsiness and decrements in cognitive performance that are associated with PMZ administration (50 mg IM on the ground, are absent or less pronounced in space suggesting I that-the bioavailability and/or pharmacodynamic behavior of PMZ may be altered during space flight. There are limited flight opportunities available for clinical research in space, the NRA-99, therefore, solicits research required to improve, or answer specific questions about in-flight diagnosis, therapy, and post-flight rehabilitation. We propose here, to establish a noninvasive method for pharmacodynamic and therapeutic assessment of PMZ. The specific objectives of the proposed research are to, 1. Establish a saliva to plasma ratio of PMZ after administration, 2. Estimate the relative bioavailability of the three flight-specific dosage forms of PMZ, and 3. Establish the dose-response relationship of PMZ. We will estimate the bioavailability of intramuscular injection (IM), oral tablets and rectal suppositories in normal subjects during ambulatory and antiorthostatic; bed rest (ABR) conditions using novel stable isotope techniques. Drowsiness, cognitive performance and salivary flow rate will be measured as a function of circulating drug concentrations after administration of three IM doses of PMZ. We will compare and contrast the bioavailability of PMZ during normal and ABR conditions to examine whether or not ABR can simulate changes in drug, absorption and availability similar to those anticipated in a microgravity environment. Results of this study will validate methods for an approved study with this medication awaiting a flight opportunity for manifestation. These data will also provide the much needed information on the dynamics and therapeutic index. of this medication and their implications on crew fatigue and performance in space. Key words

Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol).

PubMed

Chan, Lingtak-Neander; Anderson, Gail D

2014-12-01

Ethanol (alcohol) is one of the most widely used legal drugs in the world. Ethanol is metabolized by alcohol dehydrogenase (ADH) and the cytochrome P450 (CYP) 2E1 drug-metabolizing enzyme that is also responsible for the biotransformation of xenobiotics and fatty acids. Drugs that inhibit ADH or CYP2E1 are the most likely theoretical compounds that would lead to a clinically significant pharmacokinetic interaction with ethanol, which include only a limited number of drugs. Acute ethanol primarily alters the pharmacokinetics of other drugs by changing the rate and extent of absorption, with more limited effects on clearance. Both acute and chronic ethanol use can cause transient changes to many physiologic responses in different organ systems such as hypotension and impairment of motor and cognitive functions, resulting in both pharmacokinetic and pharmacodynamic interactions. Evaluating drug interactions with long-term use of ethanol is uniquely challenging. Specifically, it is difficult to distinguish between the effects of long-term ethanol use on liver pathology and chronic malnutrition. Ethanol-induced liver disease results in decreased activity of hepatic metabolic enzymes and changes in protein binding. Clinical studies that include patients with chronic alcohol use may be evaluating the effects of mild cirrhosis on liver metabolism, and not just ethanol itself. The definition of chronic alcohol use is very inconsistent, which greatly affects the quality of the data and clinical application of the results. Our study of the literature has shown that a significantly higher volume of clinical studies have focused on the pharmacokinetic interactions of ethanol and other drugs. The data on pharmacodynamic interactions are more limited and future research addressing pharmacodynamic interactions with ethanol, especially regarding the non-central nervous system effects, is much needed.

Pharmacodynamic response profiles of anxiolytic and sedative drugs.

PubMed

Chen, Xia; Broeyer, Freerk; de Kam, Marieke; Baas, Joke; Cohen, Adam; van Gerven, Joop

2017-05-01

Centrally-acting acutely anxiolytic drugs, such as benzodiazepines, barbiturates and gabapentinoids, affect various central nervous system (CNS) functions, which reflects not only their anxiolytic effects but also neuropsychological side-effects. To validate the pharmacodynamic biomarkers for GABA-ergic anxiolytics, this study determined the pharmacodynamics of two anxiolytics and a nonanxiolytic control, and linked them to their anxiolytic and sedative effects, during an anxiety-challenge study day. Twenty healthy volunteers were randomized in this placebo-controlled, double-blind, four-way cross-over study with single-dose alprazolam (1 mg), diphenhydramine (50 mg), pregabalin (200 mg) or placebo. The Neurocart was used between repeated fear-potentiated startle assessments. Thus, the potential influence of anxiety on CNS pharmacodynamic markers could be examined. Compared to placebo, VAS calmness increased with alprazolam (2.0 mm) and pregabalin (2.5 mm) but not with diphenhydramine. Saccadic peak velocity (SPV) declined after alprazolam (-57 ° s -1 ) and pregabalin (-28 ° s -1 ), more than with diphenhydramine (-14 ° s -1 ); so did smooth pursuit. The average responses of SPV and smooth pursuit were significantly correlated with the drug-induced increases in VAS calmness . The SPV-relative responses of VAS alertness , body-sway and adaptive-tracking also differed among alprazolam, pregabalin and diphenhydramine. Compared with the antihistaminergic sedative diphenhydramine, alprazolam and pregabalin caused larger SPV reduction, which was correlated with simultaneous improvement of subjective calmness, during a study day in which anxiety was stimulated repeatedly. The different effect profiles of the three drugs are in line with their pharmacological distinctions. These findings corroborate the profiling of CNS effects to demonstrate pharmacological selectivity, and further support SPV as biomarker for anxiolysis involving GABA-ergic neurons. The

Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance.

PubMed

Mathieu, Chantal; Kozlovski, Plamen; Paldánius, Päivi M; Foley, James E; Modgill, Vikas; Evans, Marc; Serban, Carmen

2017-08-01

Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.

[New method for analyzing pharmacodynamic material basis of traditional Chinese medicines by using specific knockout technology with monoclonal antibodies].

PubMed

Zhao, Yan; Qu, Hui-Hua; Wang, Qing-Guo

2013-09-01

Study on pharmacodynamic material basis of traditional Chinese medicines is one of the key issues for the modernization of traditional Chinese medicine. Having introduced the monoclonal antibody technology into the study on pharmacodynamic material basis of traditional Chinese medicines, the author prepared the immunoaffinity chromatography column by using monoclonal antibodies in active components of traditional Chinese medicines, so as to selectively knock out the component from herbs or traditional Chinese medicine compounds, while preserving all of the other components and keeping their amount and ratio unchanged. A comparative study on pharmacokinetics and pharmacodynamics was made to explicitly reveal the correlation between the component and the main purpose of traditional Chinese medicines and compounds. The analysis on pharmacodynamic material basis of traditional Chinese medicines by using specific knockout technology with monoclonal antibodies is a new method for study pharmacodynamic material basis in line with the characteristics of traditional Chinese medicines. Its results can not only help study material basis from a new perspective, but also help find the modern scientific significance in single herb or among compounds of traditional Chinese medicines.

Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies.

PubMed

van den Broek, Marcel P H; Groenendaal, Floris; Egberts, Antoine C G; Rademaker, Carin M A

2010-05-01

Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro)protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmacokinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic

[Tolerance, safety and efficacy of the one-day preparation of PEG3350 + bisacodyl compared to 2 days of PEG3350 + bisacodyl in pediatric patients].

PubMed

Portillo Canizalez, Ligia Marcela; Blanco Rodriguez, Gerardo; Teyssier Morales, Gustavo; Penchyna Grub, Jaime; Trauernicht Mendieta, Sean; Zurita-Cruz, Jessie Nallely

Multiple intestinal preparations have been used in children undergoing colonoscopy, with variable limitation due to acceptance, tolerance, and proper cleaning. The objective of this study was to compare the tolerability, safety and efficacy of the colonoscopy preparation with 1 day with PEG 3350 (poliethylenglycol) (4g/kg/day) + bisacodyl compared to 2 days of preparation with PEG 3350 (2g/kg/day) + bisacodyl in pediatric patients. A clinical, randomized, and blind trial was performed. Patients aged 2 to 18 years scheduled for colonoscopy were included. Patients were randomized into two groups: 1 day of preparation with PEG 3350 4g/kg/day + bisacodyl and 2 days of preparation with PEG 3350 2g/kg/day + bisacodyl. Through a questionnaire, physical examination and endoscopic evaluation (Boston scale), the tolerance, safety and efficacy of the 2 preparations to be evaluated were determined. Student's t test was performed for quantitative variables and χ 2 for qualitative variables. There were no significant differences in compliance rates, adverse effects, and extent of colonoscopic evaluation. Tolerance and safety between the intestinal preparation for 1-day colonoscopy with PEG 3350 (4g/kg/day) + bisacodyl and the 2-day preparation with PEG 3350 (2g/kg/day) + bisacodyl were similar. The quality of cleanliness was good in both groups, being partially more effective in the 1-day group with PEG 3350 (4g/kg/day). Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Within- and between- subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects

PubMed Central

Hanna, Julia; Foster, David JR; Salter, Amy; Somogyi, Andrew A; White, Jason M; Bochner, Felix

2005-01-01

Aims To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state. Methods Six non-holder subjects were studied on three occasions at 7–16 day intervals; doses (20–170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10–12 times over a 24-h inter-dosing interval. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value. Results Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2–12.8 for pharmacodynamic measures, and 1.3–7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged ≤2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging ≤2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance. Conclusions Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1–2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population. PMID:16187972

Optimal design in pediatric pharmacokinetic and pharmacodynamic clinical studies.

PubMed

Roberts, Jessica K; Stockmann, Chris; Balch, Alfred; Yu, Tian; Ward, Robert M; Spigarelli, Michael G; Sherwin, Catherine M T

2015-03-01

It is not trivial to conduct clinical trials with pediatric participants. Ethical, logistical, and financial considerations add to the complexity of pediatric studies. Optimal design theory allows investigators the opportunity to apply mathematical optimization algorithms to define how to structure their data collection to answer focused research questions. These techniques can be used to determine an optimal sample size, optimal sample times, and the number of samples required for pharmacokinetic and pharmacodynamic studies. The aim of this review is to demonstrate how to determine optimal sample size, optimal sample times, and the number of samples required from each patient by presenting specific examples using optimal design tools. Additionally, this review aims to discuss the relative usefulness of sparse vs rich data. This review is intended to educate the clinician, as well as the basic research scientist, whom plan on conducting a pharmacokinetic/pharmacodynamic clinical trial in pediatric patients. © 2015 John Wiley & Sons Ltd.

Evaluation of the safety and tolerability profile of Sativex: is it reassuring enough?

PubMed

Wade, Derick

2012-04-01

The adoption of new drug therapies involves an assessment of risk:benefit based upon the best clinical evidence, including clinical trials but also everyday clinical practice data collection. However, in the case of Sativex, a cannabinoid medicine containing the two main active ingredients of cannabis, δ-9-tetrahydrocannabinol and cannabidiol, the picture is somewhat clouded by preconceived views regarding the world's most widely used illicit drug, herbal cannabis. In this review, I aim to look beyond these preconceptions and evaluate the body of published data concerning this medicine currently approved in different countries for the management of one of the most frequent and disabling symptoms associated with multiple sclerosis, spasticity. In particular, data relevant to areas of concern such as tolerability, safety, psychoactivity, effects on withdrawal (including possible drug tolerance) and finally the potential for abuse/dependence are evaluated. Balancing these risk factors, the main positive clinical data published over the years by the Oxford Centre for Enablement, following on from the first pilot study in 2004, are presented. Based upon our experience, the benefits that are seen initially with Sativex when treating multiple sclerosis spasticity patients are generally maintained during long-term treatment. Furthermore, following withdrawal of Sativex, symptoms often return, but, beyond this, sudden cessation is generally safe with no evidence of physiological or psychological dependence. Dose escalation has not usually been observed in clinical trials or clinical practice after the first titration weeks. Adverse effects occur relatively frequently, but they are usually mild to moderate in intensity and rarely require drug discontinuation. Overall, Sativex appears to be well-tolerated and a useful addition for patients who have failed treatment with traditional antispastic agents.

Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib

PubMed Central

Yeo, Astrid; Warren, Liling; Aponte, Jennifer; Johansson, Kelley; Barnes, Allison; MacPhee, Colin; Davies, Richard; Chissoe, Stephanie; O’Donoghue, Michelle L.; White, Harvey D.

2017-01-01

Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS

49 CFR 350.339 - What are tolerance guidelines?

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false What are tolerance guidelines? 350.339 Section 350... MOTOR CARRIER SAFETY ASSISTANCE PROGRAM Funding § 350.339 What are tolerance guidelines? Tolerance guidelines set forth the limited deviations from the FMCSRs allowed in your State's laws and regulations...

Gender differences in pharmacokinetics and pharmacodynamics of methadone substitution therapy.

PubMed

Graziani, Manuela; Nisticò, Robert

2015-01-01

Gender-related differences in the pharmacological effects of drug are an emerging topic. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of methadone, a long-acting opioid agonist that is prescribed as a treatment for opioid dependence and the management of chronic pain. We performed a search in the Medline database from 1990 to 2014 in order to find published literature related to gender differences in pharmacokinetics (PK) and pharmacodynamics (PD) of methadone. None of the studies were carried out with the primary or secondary aim to identify any gender differences in the pharmacokinetic profile of methadone. Importantly; high inter-subjects variability in PK parameters was found also intra female population. The reported differences in volume of distribution could be ascribed to the physiological differences between men and women in body weight and composition, taking into account that the dose of methadone was established irrespective of body weight of patients (Peles and Adelson, 2006). On the other hand, the few studies present in literature found no gender difference in some direct pharmacodynamic parameters. Some reports have suggested that female gender is associated with an increased risk for long-QT-related cardiac arrhythmias in methadone maintenance subjects. Even though it may be too simplistic to expect variability only in one parameter to explain inter-individual variation in methadone response, we believe that a better knowledge of gender-related differences might have significant implications for better outcomes in opioid dependence substitution therapy in women.

Pharmacodynamic Profile of Tramadol in Humans: Influence of Naltrexone Pretreatment

PubMed Central

Stoops, William W.; Lofwall, Michelle R.; Nuzzo, Paul A.; Craig, Lori B.; Siegel, Anthony J.; Walsh, Sharon L.

2012-01-01

Rationale Tramadol is a prescription analgesic that activates mu opioid and monoamine receptor systems. Tramadol is thought to have limited abuse potential compared to mu opioid agonists, but laboratory data indicate that it shares some of their pharmacodynamic effects. Objectives This study evaluated the effect of mu opioid receptor blockade with naltrexone on the pharmacodynamic action of tramadol in humans. Methods This inpatient, double-blind, randomized, within-subject study examined the effects of oral placebo, tramadol (87.5, 175 and 350 mg) and hydromorphone (4 and 16 mg; positive control) after 1 hr pretreatment with oral naltrexone (0 and 50 mg). Ten recreational opioid users completed the study. Pharmacodynamic effects were measured before and for 7 hr after initial drug administration. Results Lower doses of tramadol and hydromorphone were generally placebo-like. Hydromorphone (16 mg) produced prototypic mu opioid agonist-like effects that were blocked by naltrexone. Tramadol (350 mg) produced miosis and increased ratings of “Good Effects” and “Liking ,” but also increased ratings of “Bad Effects.” Naltrexone reversed tramadol-induced physiological effects and mydriasis emerged, but unlike results with hydromorphone, naltrexone only partially attenuated tramadol’s positive subjective effects and actually enhanced several unpleasant subjective ratings. Conclusions Naltrexone can be used to disentangle the mixed neuropharmacological actions of tramadol. High dose tramadol produces a mixed profile of effects. These data suggest that both mu and non-mu opioid actions play a role in tramadol’s subjective profile of action. PMID:22623016

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects

PubMed Central

Jung, Jin Ah; Lee, Soo-Yun; Kim, Jung-Ryul; Ko, Jae-Wook; Jang, Seong Bok; Nam, Su Youn; Huh, Wooseong

2015-01-01

Purpose Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Subjects and methods Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment. Results For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873−0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632−0.9701) for area under the concentration–time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946−1.0884) and 1.0072 (0.8893−1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events. Conclusion The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

PubMed Central

2013-01-01

Background This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Methods Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Results Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. Conclusions Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile. Trial registration NCT00687934 PMID:23530663

Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability

PubMed Central

Bigaeva, Emilia; van Doorn, Eva; Liu, Heng; Hak, Eelko

2016-01-01

Background and Objectives QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials. Methods A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality. Results Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04–6.24). No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10–15.35 and RR 2.55, 95% CI 1.41–4.59, respectively). ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08–10.97). Conclusions Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non

Pharmacodynamic-pharmacokinetic integration as a guide to medicinal chemistry.

PubMed

Gabrielsson, Johan; Fjellström, Ola; Ulander, Johan; Rowley, Michael; Van Der Graaf, Piet H

2011-01-01

A primary objective of pharmacokinetic-pharmacodynamic (PKPD) reasoning is to identify key in vivo drug and system proper¬ties, enabling prediction of the magnitude and time course of drug responses under physiological and pathological conditions in animals and man. Since the pharmacological response generated by a drug is highly dependent on the actual system used to study its action, knowledge about its potency and efficacy at a given concentration or dose is insufficient to obtain a proper understanding of its pharmacodynamic profile. Hence, the output of PKPD activities extends beyond the provision of quantitative measures (models) of results, to the design of future protocols. Furthermore, because PKPD integrates DMPK (e.g. clearance) and pharmacology (e.g. potency),it provides an anchor point for compound selection, and, as such, should be viewed as an important weapon in medicinal chemistry. Here we outline key PK concepts relevant to PD, and then consider real-life experiments to illustrate the importance to the medicinal chemist of data obtained by PKPD. Useful assumptions and potential pitfalls are described, providing a holistic view of the plethora of determinants behind in vitro-in vivo correlations. By condensing complexity to simplicity, there are not only consequences for experimental design, and for the ranking and design of compounds, but it is also possible to make important predictions such as the impact of changes in drug potency and kinetics. In short, by using quantitative methods to tease apart pharmacodynamic complexities such as temporal differences and changes in plasma protein binding, it is possible to target the changes necessary for improving a compound's profile.

Long-Acting β2-Agonists in Asthma: Enantioselective Safety Studies are Needed.

PubMed

Jacobson, Glenn A; Raidal, Sharanne; Hostrup, Morten; Calzetta, Luigino; Wood-Baker, Richard; Farber, Mark O; Page, Clive P; Walters, E Haydn

2018-05-01

Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without ICS. LABAs clearly demonstrate effective bronchodilatation and steroid-sparing activity, but long-term treatment can lead to tolerance of their bronchodilator effects. There are also concerns with regard to the effects of LABAs on bronchial hyperresponsiveness (BHR), where long-term use is associated with increased BHR and loss of bronchoprotection. A complicating factor is that formoterol and salmeterol are both chiral compounds, usually administered as 50:50 racemic (rac-) mixtures of two enantiomers. The chiral nature of these compounds has been largely forgotten in the debate regarding LABA safety and effects on BHR, particularly that (S)-enantiomers of β2-agonists may be deleterious to asthma control. LABAs display enantioselective pharmacokinetics and pharmacodynamics. Biological plausibility of the deleterious effects of β2-agonists (S)-enantiomers is provided by in vitro and in vivo studies from the short-acting β2-agonist (SABA) salbutamol. Supportive clinical findings include the fact that patients in emergency departments who demonstrate a blunted response to salbutamol are more likely to benefit from (R)-salbutamol than rac-salbutamol, and resistance to salbutamol appears to be a contributory mechanism in rapid asthma deaths. More effort should therefore be applied to investigating potential enantiospecific effects of LABAs on safety, specifically bronchoprotection. Safety studies directly assessing the effects of LABA (S)-enantiomers on BHR are long overdue.

Evaluation of the Safety and Tolerability of Conjunctival Ring for Posterior Segment of the Eye.

PubMed

Kinoshita, Satoshi; Ohguchi, Takeshi; Noda, Kousuke; Murata, Miyuki; Yasueda, Shin-Ichi; Obata, Haruka; Matsunaga, Toru; Fukushima, Tsutomu; Kanda, Atsuhiro; Ishida, Susumu

2017-08-01

To evaluate the safety and tolerability of conjunctival rings (CRs), a novel device for drug delivery to the posterior segment of the eye. In animal studies, CRs containing 5% dexamethasone sodium phosphate (DSP) or vehicle solution were placed on the right and left eyes of C57BL/6J mice, respectively. Contact lenses (CLs) containing vehicle solution were used as a control. Twenty-four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production (Schirmer I test), tear film break-up time and fluorescein staining scores of the cornea (scores ranging from 0 to 3) and conjunctiva (scores ranging from 0 to 6) were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated. In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. In the preclinical safety evaluation of CR for humans, ophthalmic examination revealed that CR caused no significant changes in all the parameters investigated including corneal curvature (p = 0.77), corneal thickness (p = 0.96), intraocular pressure (p = 0.59), visual acuity (p = 0.14), Schirmer I test results (p = 0.76), tear film break-up time (p = 0.68), corneal fluorescein staining scores (p = 0.64), and conjunctival fluorescein staining scores (p = 0.52). The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously. The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases.

Long-Acting C-Terminal Peptide-Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children.

PubMed

Zelinska, Nataliya; Iotova, Violeta; Skorodok, Julia; Malievsky, Oleg; Peterkova, Valentina; Samsonova, Lubov; Rosenfeld, Ron G; Zadik, Zvi; Jaron-Mendelson, Michal; Koren, Ronit; Amitzi, Leanne; Raduk, Dmitri; Hershkovitz, Oren; Hart, Gili

2017-05-01

Daily injections are required for growth hormone (GH) replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients. C-terminal peptide-modified human GH (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children. A multicenter, open-label, randomized, controlled phase 2 study in children with GHD, evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of three different weekly MOD-4023 doses, compared with daily recombinant human GH (r-hGH). The trial was conducted in 14 endocrinology centers in Europe. Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 (N = 42) or r-hGH (N = 11). C-terminal peptide-modified hGH (MOD-4023) was administered weekly at a dose of either 0.25, 0.48, or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk. MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH. Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment. IGF-I standard deviation score for MOD-4023 did not exceed +2. All MOD-4023 cohorts demonstrated adequate catch-up growth. The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH. No serious adverse events were observed during MOD-4023 treatment, and its tolerability was consistent with known properties of r-hGH. This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile. This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023. Copyright © 2017 by the Endocrine Society

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

PubMed

Kazierad, D J; Bergman, A; Tan, B; Erion, D M; Somayaji, V; Lee, D S; Rolph, T

2016-08-01

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia. © 2016 John Wiley & Sons Ltd.

Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development.

PubMed

Clark, Amy S; Karasic, Thomas B; DeMichele, Angela; Vaughn, David J; O'Hara, Mark; Perini, Rodolfo; Zhang, Paul; Lal, Priti; Feldman, Michael; Gallagher, Maryann; O'Dwyer, Peter J

2016-02-01

Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naïve and endocrine therapy-resistant metastatic settings. Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.

Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans

PubMed Central

Maccecchini, Maria L; Chang, Mee Young; Pan, Catherine; John, Varghese; Zetterberg, Henrik

2012-01-01

Aim A first in human study to evaluate tolerability and pharmacokinetics followed by an early proof of mechanism (POM) study to determine whether the small orally, available molecule, Posiphen tartrate (Posiphen), lowers secreted (s) amyloid-β precursor protein (APP) α and -β, amyloid-β peptide (Aβ), tau (τ) and inflammatory markers in CSF of patients with mild cognitive impairment (MCI). Study design Posiphen single and multiple ascending dose phase 1 randomised, double blind, placebo-controlled safety, tolerance, pharmacokinetic studies were undertaken in a total of 120 healthy volunteers to define a dose that was then used in a small non-randomised study of five MCI subjects, used as their own controls, to define target engagement. Main outcome measures Pharmacodynamic: sAPPα, sAPPβ, Aβ42, τ (total (t) and phosphorylated (p)) and inflammatory marker levels were time-dependently measured over 12 h and compared prior to and following 10 days of oral Posiphen treatment in four MCI subjects who completed the study. Pharmacokinetic: plasma and CSF drug and primary metabolite concentrations with estimated brain levels extrapolated from steady-state drug administration in rats. Results Posiphen proved well tolerated and significantly lowered CSF levels of sAPPα, sAPPβ, t-τ, p-τ and specific inflammatory markers, and demonstrated a trend to lower CSF Aβ42. Conclusions These results confirm preclinical POM studies, demonstrate that pharmacologically relevant drug/metabolite levels reach brain and support the continued clinical optimisation and evaluation of Posiphen for MCI and Alzheimer's disease. PMID:22791904

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps

PubMed Central

Kelly, Lauren E; Sinha, Yashwant; Barker, Charlotte I S; Standing, Joseph F; Offringa, Martin

2018-01-01

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families. PMID:29667952

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

PubMed Central

Clearie, Karine L; Williamson, Peter A; Meldrum, Karen; Gillen, Michael; Carlsson, Lars-Goran; Carlholm, Marie; Ekelund, Jan; Lipworth, Brian J

2011-01-01

AIMS A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC24h[area under the concentration-time curve (0–24 h)], budesonide AUC0–12h and Cmax. Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC20 (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS In the pharmacokinetic study, there were no differences in cortisol, AUC0–12h[area under the concentration-time curve (0–12 h)], Tmax (time to maximum concentration) or Cmax (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC24h was 1.02 (95% confidence interval 0.93–1.11) and budesonide AUC0–12h was 1.03 (90% confidence interval 0.9–1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC20 (provocative concentration of methacholine needed to produce a 20% fall in FEV1) with a relative potency ratio of 1.10 (95% confidence interval 0.49–2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary

A 12-Month Open-Label Extension Study of the Safety and Tolerability of Lisdexamfetamine Dimesylate for Major Depressive Disorder in Adults.

PubMed

Richards, Cynthia; Iosifescu, Dan V; Mago, Rajnish; Sarkis, Elias; Geibel, Brooke; Dauphin, Matthew; McIntyre, Roger S; Weisler, Richard; Brawman-Mintzer, Olga; Gu, Joan; Madhoo, Manisha

2018-06-16

Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20-70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and

A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study.

PubMed

Chung, Hyewon; Oh, Jaeseong; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Chung, Jae-Yong

2018-01-01

The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated. The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms. This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin. ClinicalTrials.gov NCT02712619.

Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban

PubMed Central

Frost, Charles; Shenker, Andrew; Gandhi, Mohit D; Pursley, Janice; Barrett, Yu Chen; Wang, Jessie; Zhang, Donglu; Byon, Wonkyung; Boyd, Rebecca A; LaCreta, Frank

2014-01-01

Aim To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor). Method In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio [INR] and arachidonic acid–induced platelet aggregation [AAI-PA]). Adverse events, bleeding time and routine safety assessments were also evaluated. Results Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation [SD]) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with apixaban alone, 4.4 [1.0] vs. 2.7 [0.7] IU ml−1, consistent with the apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean [SD] bleeding time was higher following co-administration (9.1 [4.1] min) compared with either agent alone (5.8 [2.3] and 6.9 [2.6] min for apixaban and naproxen, respectively). Conclusion Co-administration of naproxen with apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen. PMID:24697979

Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban.

PubMed

Frost, Charles; Shenker, Andrew; Gandhi, Mohit D; Pursley, Janice; Barrett, Yu Chen; Wang, Jessie; Zhang, Donglu; Byon, Wonkyung; Boyd, Rebecca A; LaCreta, Frank

2014-10-01

To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor). In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio [INR] and arachidonic acid-induced platelet aggregation [AAI-PA]). Adverse events, bleeding time and routine safety assessments were also evaluated. Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation [SD]) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with apixaban alone, 4.4 [1.0] vs. 2.7 [0.7] IU ml(-1) , consistent with the apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean [SD] bleeding time was higher following co-administration (9.1 [4.1] min) compared with either agent alone (5.8 [2.3] and 6.9 [2.6] min for apixaban and naproxen, respectively). Co-administration of naproxen with apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen. © 2014 The British Pharmacological Society.

A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State

PubMed Central

Chen, Chun Lin; Desai-Krieger, Daksha; Ortiz, Stephan; Kerolous, Majid; Wright, Harold M.; Ghahramani, Parviz

2015-01-01

Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18–45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol–valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol–valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol–valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms. PMID:25853236

Structured versus long-chain triglycerides: a safety, tolerance, and efficacy randomized study in colorectal surgical patients.

PubMed

Bellantone, R; Bossola, M; Carriero, C; Malerba, M; Nucera, P; Ratto, C; Crucitti, P; Pacelli, F; Doglietto, G B; Crucitti, F

1999-01-01

After trauma or surgery, researchers have suggested that medium-chain triglycerides have metabolic advantages, although they are toxic in large doses. To try to reduce this potential toxicity, structured lipids, which provide a higher oxidation rate, faster clearance from blood, improved nitrogen balance, and less accumulation in the reticuloendothelial system, could be used. Therefore, we evaluated, through a blind randomized study, the safety, tolerance, and efficacy of structured triglycerides, compared with long-chain triglycerides (LCT), in patients undergoing colorectal surgery. Nineteen patients were randomized to receive long-chain or structured triglycerides as a lipid source. They received the same amount of calories (27.2/kg/d), glucose (4 g/kg/d), protein (0.2 g/kg/d), and lipids (11.2 kcal/kg/d). Patients were evaluated during and after the treatment for clinical and laboratory variables, daily and cumulative nitrogen balance, urinary excretion of 3-methyl-histidine, and urinary 3-methylhistidine/creatinine ratio. No adverse effect that required the interruption of the treatment was observed. Triglyceride levels and clinical and laboratory variables were similar in the two groups. A predominantly positive nitrogen balance was observed from day 2 until day 5 in the LCT group and from day 1 until day 4 in the structured triglycerides group. The cumulative nitrogen balance (in grams) for days 1 to 3 was 9.7+/-5.2 in the experimental group and 4.4+/-11.8 in the control group (p = .2). For days 1 to 5 it was 10.7+/-10.5 and 6.5+/-17.9 (p = .05), respectively. The excretion of 3-methylhistidine was higher in the control group but decreased in the following days and was similar to the experimental group on day 5. This study represents the first report in which structured triglycerides are administered in postoperative patients to evaluate safety, tolerance, and efficacy. It suggests that Fe73403 is safe, well tolerated, and efficacious in terms of nitrogen

Safety profile of levetiracetam.

PubMed

Arroyo, Santiago; Crawford, Pamela

2003-05-01

A good balance between safety and tolerability is necessary for an antiepileptic drug (AED) to be successful in the management of patients with epilepsy. Levetiracetam is one of the new generation of AEDs licensed as an add-on therapy for the treatment of patients with partial-onset seizures. Leveti-racetam's mechanisms of action are not fully understood. Controlled clinical trials, open-label studies, and postmarketing surveillance indicate that leveti-racetam has a favorable safety profile characterized by little effect on vital signs or clinical laboratory values, reported adverse events that are mild to moderate, and no known drug-drug interactions. The tolerability of levetiracetam may extend to both pediatric and elderly patients based on analyses of small numbers of patients. Tolerability is maintained over the long term. Levetirac-etam does not appear to have a different safety profile in learning-disabled patients. Levetiracetam appears to have a good balance between tolerability and efficacy in the treatment of a wide variety of patients with partial epilepsy.

Pharmacokinetics, safety and tolerability of mipomersen in healthy Japanese volunteers and comparison with Western subjects.

PubMed

Li, Zhaoyang; Hard, Marjie L; Andersen, Grit; Pabst, Günther; Wagener, Gilbert; Singh, Tejdip; Chin, Wai; Culm-Merdek, Kerry; Boltje, Ingrid; von Moltke, Lisa L

2014-04-01

To characterize the safety, tolerability, pharmacokinetics (PK) and dose proportionality of mipomersen after single subcutaneous (SC) administration to Japanese healthy subjects; and to compare the PK profiles of Japanese and Western subjects. 20 healthy first-generation Japanese male subjects were enrolled into one of three treatment cohorts (50, 100 and 200 mg SC) in a dose-escalation design. Within each cohort, subjects were randomized in a 4 : 1 ratio to receive mipomersen or placebo. Mipomersen was absorbed rapidly after SC administration; median tmax varied between 2 and 3 hours. After reaching peak levels, plasma concentrations of mipomersen decayed multiphasically with an initial distribution t1/2 in several hours and a terminal t1/2 of 261 - 393 hours. Mean Cmax increased in a dose-linear manner while all mean AUC from time 0 to different cut points increased slightly more than dose proportionally. Although mean terminal t1/2 varied in the dose range tested, it did not show dose-dependence. The PK profiles of mipomersen in Japanese subjects are similar to those observed in Western subjects. A single SC dose of 50 mg, 100 mg and 200 mg mipomersen was well tolerated by male Japanese subjects. Single SC doses of 50 - 200 mg were safe and well tolerated when administered to Japanese subjects. Comparison of PK between Japanese and Western subjects does not support any need for dose adjustment in Japanese population in future clinical development.

Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation.

PubMed

Caprioli, Giovanni; Mammoli, Valerio; Ricciutelli, Massimo; Sagratini, Gianni; Ubaldi, Massimo; Domi, Esi; Mennuni, Laura; Sabatini, Chiara; Galimberti, Chiara; Ferrari, Flora; Milia, Chiara; Comi, Eleonora; Lanza, Marco; Giannella, Mario; Pigini, Maria; Del Bello, Fabio

2015-12-15

Tolerance to opioid administration represents a serious medical alert in different chronic conditions. This study compares the effects of the imidazoline compounds 1, 2, and 3 on morphine tolerance in an animal model of inflammatory pain in the rat. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to α2-adrenoceptors, imidazoline I2 receptors, or both systems, respectively. Such compounds have been tested in vivo by measuring the paw withdrawal threshold to mechanical pressure after complete Freund's adjuvant injection. To determine the ligand levels in rat plasma, an HPLC-mass spectrometry method has been developed. All the compounds significantly reduced the induction of morphine tolerance, showing different potency and duration of action. Indeed, the selective imidazoline I2 receptor interaction (2) restored the analgesic response by maintaining the same time-dependent profile observed after a single morphine administration. Differently, the selective α2C-adrenoceptor activation (1) or the combination between α2C-adrenoceptor activation and imidazoline I2 receptor engagement (3) promoted a change in the temporal profile of morphine analgesia by maintaining a mild but long lasting analgesic effect. Interestingly, the kinetics of compounds in rat plasma supported the pharmacodynamic data. Therefore, this study highlights that both peculiar biological profile and bioavailability of such ligands complement each other to modulate the reduction of morphine tolerance. Based on these observations, 1-3 can be considered useful leads in the design of new drugs able to turn off the undesired tolerance induced by opioids. Copyright © 2015 Elsevier B.V. All rights reserved.

Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol.

PubMed

Tuk, Bert; van Gool, Toon; Danhof, Meindert

2002-06-01

The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ1 receptor subtype selective agonist zolpidem have been determined in the rat in vivo, using an integrated pharmacokinetic-pharmacodynamic approach. Ethanol was administered as a constant rate infusion resulting in constant plasma concentrations of 0.5 g/l. The pharmacokinetics and pharmacodynamics of midazolam, bretazenil, and zolpidem were determined following an intravenous infusion of 5.0, 2.5, and 18 mg/kg respectively. The amplitude in the 11.5-30 Hz frequency band of the EEG was used as measure of the pharmacological effect. For each of the benzodiazepines the concentration-EEG effect relationship could be described by the sigmoid Emax pharmacodynamic model. Significant differences in both EC50 and Emax were observed. The values of the EC50 were 76 +/- 11, 12 +/- 3, and 512 +/- 116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the Emax were 113 +/- 9, 44 +/- 3, and 175 +/- 10 microV/s. In the presence of ethanol the values of the EC50 of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for Emax and Hill-factor were unchanged Due to a large interindividual variability no significant change in EC50 was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant KPD for all three drugs, indicating that changes in EC50 can be explained entirely by a change in the apparent affinity constant KPD without concomitant changes in the efficacy parameter ePD and the stimulus-effect relationship. The findings of this study show that the pharmacodynamic interactions with a low dose of ethanol in vivo are qualitatively and quantitatively similar for benzodiazepine receptor full agonists, partial agonists, and benzodiazepine BZ1 receptor subtype selective

Induction Speed Is Not a Determinant of Propofol Pharmacodynamics

PubMed Central

Doufas, Anthony G.; Bakhshandeh, Maryam; Bjorksten, Andrew R.; Shafer, Steven L.; Sessler, Daniel I.

2005-01-01

Summary We used individual pharmacodynamic modeling to demonstrate that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate of propofol. Background Evidence suggests that the rate at which they are infused may influence plasma-effect site equilibration of intravenous anesthetics. We used 5 different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. We concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration. Methods With Human Studies Committee approval, 18 healthy volunteers received 5 consecutive target-controlled propofol infusions. During each infusion the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 μg·ml−1·min−1. Bispectral index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM. Results Once the correct rate of plasma-effect site equilibration (ke0) was determined for each individual (ke0 = 0.17 min−1, time-to-peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of rise of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness. Conclusions Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM appears useful as an automated measure of sedation and may provide the basis for automated monitoring and

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

PubMed Central

Bauer, Seth R.; Salem, Charbel; Connor, Michael J.; Groszek, Joseph; Taylor, Maria E.; Wei, Peilin; Tolwani, Ashita J.

2012-01-01

Summary Background and objectives Current recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions. Design, setting, participants, & measurements A multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters. Results Forty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h−1, intraquartile range=0.052 h−1) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered. Conclusions There is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic

Pharmacokinetics, pharmacodynamics, and pharmacogenomics of immunosuppressants in allogeneic hematopoietic cell transplantation: Part II

PubMed Central

McCune, Jeannine S.; Bemer, Meagan J.; Long-Boyle, Janel

2015-01-01

Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article, part II, we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. There are several studies demonstrating that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared to MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include “–omics” based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics and proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses. PMID:26620047

[Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project].

PubMed

Dalle Carbonare, L; Bertoldo, F; Lo Cascio, V

2009-01-01

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Despite evidence supporting the anti-fracture efficacy of aminobisphosphonates approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within the first year. Poor compliance is associated with negative outcomes, including increased fracture risk. Tolerability and safety are among the causes of poor compliance. Intravenous bisphosphonates avoids the gastrointestial intolerance and the complex dosing instruction of the oral route ensuring full compliance which may provide improved efficacy. However, there are some concerns regarding potent intravenous bisphosphonates as zoledronic acid with respect to tolerability, mainly the acute phase response and to safety, mainly a theoretical risk of over suppression of bone turnover, renal toxicity and osteonecrosis of the jaw. In the HORIZON study, 152 patients on active treatment (82) or placebo (70) underwent to a bone biopsy after double tetracycline labeling. Bone biopsies (iliac crest) were obtained at the final visit at month 36, 1 year after the last infusion. The biopsies were analyzed by histomorphometry on bone sections and by micro-CT (microCT) analysis. One hundred forthy-three biopsies (76 zoledronic acid, 67 placebo) had at least one microCT parameter measured and 111 were available for quantitative histomorphometry (59 zoledronic acid, 52 placebo). Micro-CT analysis of bone structure revealed higher trabecular bone volume (BV/TV), decreased trabecular separation (Tb.Sp), and a strong trend towards improvement in connectivity density in biopsies obtained from patients treated with zoledronic acid, indicating preservation of trabecular bone structure with respect to placebo. Histomorphometric analysis obtained from patients treated with zoledronic acid exhibited reduction of bone turnover, as suggested by decreased activation frequency (Ac.F) by 63%, mineralizing

[Systemic safety following intravitreal injections of anti-VEGF].

PubMed

Baillif, S; Levy, B; Girmens, J-F; Dumas, S; Tadayoni, R

2018-03-01

The goal of this manuscript is to assess data suggesting that intravitreal injection of anti-vascular endothelial growth factors (anti-VEGFs) could result in systemic adverse events (AEs). The class-specific systemic AEs should be similar to those encountered in cancer trials. The most frequent AE observed in oncology, hypertension and proteinuria, should thus be the most common expected in ophthalmology, but their severity should be lower because of the much lower doses of anti-VEGFs administered intravitreally. Such AEs have not been frequently reported in ophthalmology trials. In addition, pharmacokinetic and pharmacodynamic data describing systemic diffusion of anti-VEGFs should be interpreted with caution because of significant inconsistencies reported. Thus, safety data reported in ophthalmology trials and pharmacokinetic/pharmacodynamic data provide robust evidence that systemic events after intravitreal injection are very unlikely. Additional studies are needed to explore this issue further, as much remains to be understood about local and systemic side effects of anti-VEGFs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders.

PubMed

Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; De Maeyer, J H; Stanghellini, V

2012-04-01

The nonselective 5-HT(4) receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT(4) agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT(4) agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT(4) agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT(1) receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT(4) agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT(4) agonists with no hERG or 5-HT(1) affinity (renzapride, clebopride, mosapride). 5-HT(4) agonists for GI disorders differ in chemical structure and selectivity for 5-HT(4) receptors. Selectivity for 5-HT(4) over non-5-HT(4) receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT(4) agonists may offer improved safety to treat patients with impaired GI motility. © 2012 Blackwell Publishing Ltd.

Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders

PubMed Central

Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; Maeyer, J H; Stanghellini, V

2012-01-01

Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility. PMID:22356640

76 FR 22620 - Triflusulfuron-Methyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-22

... under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This regulation is effective April 22... Determination of Safety Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit... determination on aggregate exposure for triflusulfuron-methyl, including exposure resulting from the tolerances...

Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs.

PubMed

Löscher, Wolfgang; Schmidt, Dieter

2006-08-01

Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most first-generation AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of

Accuracy, safety, and tolerability of tissue collection by Cytosponge vs endoscopy for evaluation of eosinophilic esophagitis.

PubMed

Katzka, David A; Geno, Debra M; Ravi, Anupama; Smyrk, Thomas C; Lao-Sirieix, Pierre; Miremadi, Ahmed; Miramedi, Ahmed; Debiram, Irene; O'Donovan, Maria; Kita, Hirohito; Kephart, Gail M; Kryzer, Lori A; Camilleri, Michael; Alexander, Jeffrey A; Fitzgerald, Rebecca C

2015-01-01

Management of eosinophilic esophagitis (EoE) requires repeated endoscopic collection of mucosal samples to assess disease activity and response to therapy. An easier and less expensive means of monitoring of EoE is required. We compared the accuracy, safety, and tolerability of sample collection via Cytosponge (an ingestible gelatin capsule comprising compressed mesh attached to a string) with those of endoscopy for assessment of EoE. Esophageal tissues were collected from 20 patients with EoE (all with dysphagia, 15 with stricture, 13 with active EoE) via Cytosponge and then by endoscopy. Number of eosinophils/high-power field and levels of eosinophil-derived neurotoxin were determined; hematoxylin-eosin staining was performed. We compared the adequacy, diagnostic accuracy, safety, and patient preference for sample collection via Cytosponge vs endoscopy procedures. All 20 samples collected by Cytosponge were adequate for analysis. By using a cutoff value of 15 eosinophils/high power field, analysis of samples collected by Cytosponge identified 11 of the 13 individuals with active EoE (83%); additional features such as abscesses were also identified. Numbers of eosinophils in samples collected by Cytosponge correlated with those in samples collected by endoscopy (r = 0.50, P = .025). Analysis of tissues collected by Cytosponge identified 4 of the 7 patients without active EoE (57% specificity), as well as 3 cases of active EoE not identified by analysis of endoscopy samples. Including information on level of eosinophil-derived neurotoxin did not increase the accuracy of diagnosis. No complications occurred during the Cytosponge procedure, which was preferred by all patients, compared with endoscopy. In a feasibility study, the Cytosponge is a safe and well-tolerated method for collecting near mucosal specimens. Analysis of numbers of eosinophils/high-power field identified patients with active EoE with 83% sensitivity. Larger studies are needed to establish the

Safety and Tolerance Evaluation of Milk Fat Globule Membrane-Enriched Infant Formulas: A Randomized Controlled Multicenter Non-Inferiority Trial in Healthy Term Infants

PubMed Central

Billeaud, Claude; Puccio, Giuseppe; Saliba, Elie; Guillois, Bernard; Vaysse, Carole; Pecquet, Sophie; Steenhout, Philippe

2014-01-01

OBJECTIVE This multicenter non-inferiority study evaluated the safety of infant formulas enriched with bovine milk fat globule membrane (MFGM) fractions. METHODS Healthy, full-term infants (n = 119) age ≤14 days were randomized to standard infant formula (control), standard formula enriched with a lipid-rich MFGM fraction (MFGM-L), or standard formula enriched with a protein-rich MFGM fraction (MFGM-P). Primary outcome was mean weight gain per day from enrollment to age 4 months (non-inferiority margin: −3.0 g/day). Secondary (length, head circumference, tolerability, morbidity, adverse events) and exploratory (phospholipids, metabolic markers, immune markers) outcomes were also evaluated. RESULTS Weight gain was non-inferior in the MFGM-L and MFGM-P groups compared with the control group. Among secondary and exploratory outcomes, few between-group differences were observed. Formula tolerance rates were high (>94%) in all groups. Adverse event and morbidity rates were similar across groups except for a higher rate of eczema in the MFGM-P group (13.9% vs control [3.5%], MFGM-L [1.4%]). CONCLUSION Both MFGM-enriched formulas met the primary safety endpoint of non-inferiority in weight gain and were generally well tolerated, although a higher rate of eczema was observed in the MFGM-P group. PMID:25452707

Comparison of safety, efficacy and tolerability of dexibuprofen and ibuprofen in the treatment of osteoarthritis of the hip or knee.

PubMed

Zamani, Omid; Böttcher, Elke; Rieger, Jörg D; Mitterhuber, Johann; Hawel, Reinhold; Stallinger, Sylvia; Eller, Norbert

2014-06-01

In this observer-blinded, multicenter, non-inferiority study, 489 patients suffering from painful osteoarthritis of the hip or knee were included to investigate safety and tolerability of Dexibuprofen vs. Ibuprofen powder for oral suspension. Only patients who had everyday joint pain for the past 3 months and "moderate" to "severe" global pain intensity in the involved hip/knee of within the last 48 h were enrolled. The treatment period was up to 14 days with a control visit after 3 days. The test product was Dexibuprofen 400 mg powder for oral suspension (daily dose 800 mg) compared to Ibuprofen 400 mg powder for oral suspension (daily dose 1,600 mg). Gastrointestinal adverse drug reactions were reported in 8 patients (3.3 %) in the Dexibuprofen group and in 19 patients (7.8 %) in the Ibuprofen group. Statistically significant non-inferiority was shown for Dexibuprofen. Comparing both groups by a Chi square test showed a statistical significant lower proportion of related gastrointestinal events in the Dexibuprofen group. All analyses of secondary tolerability parameters showed the same result of a significantly better safety profile in this therapy setting for Dexibuprofen compared to Ibuprofen. The sum of pain intensity, pain relief and global assessments showed no significant difference between treatment groups. In summary, analyses revealed at least non-inferiority in terms of efficacy and a statistically significant better safety profile for the Dexibuprofen treatment.

Nanodrugs: pharmacokinetics and safety

PubMed Central

Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

2014-01-01

To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

Safety and tolerability of combination therapy vs. standard treatment alone for patients with previously treated non-small cell lung cancer | Center for Cancer Research

Cancer.gov

Dr. James Gulley is leading a team to test the safety and tolerability of the combination of nivolumab and CV301 to see if it can improve the survival for patientis with metastatic non-small cell lung cancer.  Learn more...

The Effect of Prerequisite Pharmacodynamics Course Timing on Student Performance in Pharmacotherapy Courses.

PubMed

Kelsch, Michael P; Sylvester, Robert K

2016-08-25

Objective. To evaluate the impact that decreasing the time from 12 to three months between prerequisite pharmacodynamics courses and their corresponding pharmacotherapy courses had on overall student performance in the pharmacotherapy courses measured by course examination scores. Methods. Two cohorts of second-professional year (P2) and third professional year (P3) classes, respectively, following different curriculum plans, simultaneously took two pharmacotherapy courses (infectious disease and neoplastic disease). Admission data (age, gender, prior bachelor's degree status, grade point average (GPA), Pharmacy College Admission Test (PCAT) score, and interview score) were collected to establish baseline characteristics between the two cohorts. Examination scores in the corresponding prerequisite pharmacodynamics and pharmacotherapy courses were also collected. The variable was the difference in time each cohort experienced between the prerequisite pharmacodynamics courses and the subsequent pharmacotherapy courses. Results. No difference was found in baseline admission characteristics between the two cohorts, except for increased average age, which favored the P2 cohort. In the infectious disease pharmacotherapy course, the P3 cohort performed better than the P2 cohort as measured by average examination scores. In the neoplastic disease pharmacotherapy course, the P3 cohort also achieved significant higher average examination scores than the P2 cohort. The P3 cohort achieved higher overall scores than the P2 cohort in both courses despite a longer interval between the applicable pharmacodynamic and pharmacotherapy courses (12 months vs 3 months, respectively). Conclusion. Shortening the time interval from 12 months to three months between prerequisite and requisite courses did not result in improved, or even equivalent, academic performance relative to the P2 cohort that had only a 3-month interval between courses. Placing like content closer together, as the

The Effect of Prerequisite Pharmacodynamics Course Timing on Student Performance in Pharmacotherapy Courses

PubMed Central

Sylvester, Robert K.

2016-01-01

Objective. To evaluate the impact that decreasing the time from 12 to three months between prerequisite pharmacodynamics courses and their corresponding pharmacotherapy courses had on overall student performance in the pharmacotherapy courses measured by course examination scores. Methods. Two cohorts of second-professional year (P2) and third professional year (P3) classes, respectively, following different curriculum plans, simultaneously took two pharmacotherapy courses (infectious disease and neoplastic disease). Admission data (age, gender, prior bachelor’s degree status, grade point average (GPA), Pharmacy College Admission Test (PCAT) score, and interview score) were collected to establish baseline characteristics between the two cohorts. Examination scores in the corresponding prerequisite pharmacodynamics and pharmacotherapy courses were also collected. The variable was the difference in time each cohort experienced between the prerequisite pharmacodynamics courses and the subsequent pharmacotherapy courses. Results. No difference was found in baseline admission characteristics between the two cohorts, except for increased average age, which favored the P2 cohort. In the infectious disease pharmacotherapy course, the P3 cohort performed better than the P2 cohort as measured by average examination scores. In the neoplastic disease pharmacotherapy course, the P3 cohort also achieved significant higher average examination scores than the P2 cohort. The P3 cohort achieved higher overall scores than the P2 cohort in both courses despite a longer interval between the applicable pharmacodynamic and pharmacotherapy courses (12 months vs 3 months, respectively). Conclusion. Shortening the time interval from 12 months to three months between prerequisite and requisite courses did not result in improved, or even equivalent, academic performance relative to the P2 cohort that had only a 3-month interval between courses. Placing like content closer together, as the

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients

PubMed Central

Yang, Juan; Li, Lu-jin; Wang, Kun; He, Ying-chun; Sheng, Yu-cheng; Xu, Ling; Huang, Xiao-hui; Guo, Feng; Zheng, Qing-shan

2011-01-01

Aim: To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials. Methods: Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials. Results: Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple Emax model with a fixed E0, which provided a common Emax and an approximate twofold difference in ED50 for Westerners and Asians. The PPD model was demonstrated to be stable and predictive. Conclusion: The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries. PMID:21151159

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients.

PubMed

Yang, Juan; Li, Lu-jin; Wang, Kun; He, Ying-chun; Sheng, Yu-cheng; Xu, Ling; Huang, Xiao-hui; Guo, Feng; Zheng, Qing-shan

2011-01-01

To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials. Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials. Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple E(max) model with a fixed E(0), which provided a common E(max) and an approximate twofold difference in ED(50) for Westerners and Asians. The PPD model was demonstrated to be stable and predictive. The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries.

Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients

PubMed Central

2011-01-01

Introduction Acetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook the pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation. Methods This observational, retrospective study included 68 invasively ventilated COPD patients who received one or multiple doses of 250 or 500 mg of acetazolamide during the weaning period. Among the 68 investigated patients, 207 time-serum bicarbonate observations were available for analysis. Population pharmacodynamics was modeled using a nonlinear mixedeffect model. The main covariates of interest were baseline demographic data, Simplified Acute Physiology Score II (SAPS II) at ICU admission, cause of respiratory failure, co-prescription of drugs interfering with the acid-base equilibrium, and serum concentrations of protein, creatinin, potassium and chloride. The effect of acetazolamide on serum bicarbonate levels at different doses and in different clinical conditions was subsequently simulated in silico. Results The main covariates interacting with acetazolamide pharmacodynamics were SAPS II at ICU admission (P = 0.01), serum chloride (P < 0.001) and concomitant administration of corticosteroids (P = 0.02). Co-administration of furosemide significantly decreased bicarbonate elimination. Acetazolamide induced a decrease in serum bicarbonate with a dose-response relationship. The amount of acetazolamide inducing 50% of the putative maximum effect was 117 ± 21 mg. According to our model, an acetazolamide dosage > 500 mg twice daily is required to reduce serum bicarbonate concentrations > 5 mmol/L in the presence of high serum chloride levels or coadministration of systemic corticosteroids or furosemide. Conclusions This study identified several covariates that influenced acetazolamide pharmacodynamics and could allow a better

Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials.

PubMed

Schoenfeld, P; Pimentel, M; Chang, L; Lembo, A; Chey, W D; Yu, J; Paterson, C; Bortey, E; Forbes, W P

2014-05-01

The efficacy of rifaximin, a nonsystemic, gut-targeted antibiotic for reducing non-constipation-predominant irritable bowel syndrome (non-C IBS) symptoms, has been demonstrated in one phase 2b and two phase 3 randomised, double-blind, placebo-controlled trials, but detailed data about rifaximin safety and tolerability during treatment and subsequent follow-up periods are lacking. To assess and determine the frequency of rifaximin and placebo adverse events (AEs) in phase 2b and phase 3 non-C IBS trials. A post hoc pooled safety analysis of the phase 2b (rifaximin 275, 550, and 1100 mg twice daily for 2 weeks; 550 mg twice daily for 4 weeks) and phase 3 (rifaximin 550 mg three times daily for 2 weeks) studies was performed. Data on treatment and post-treatment AEs were collected. Patients were followed up for 12 weeks and 10 weeks post-treatment in the phase 2b and phase 3 trials, respectively. Patients receiving rifaximin (n = 1103) and placebo (n = 829) had a similar incidence of drug-related AEs (12.1% vs. 10.7%), serious AEs (1.5% vs. 2.2%), drug-related AEs resulting in study discontinuation (0.8% vs. 0.8%), gastrointestinal-associated AEs (12.2% vs. 12.2%) and infection-associated AEs (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis or deaths. The safety and tolerability profile of rifaximin during treatment and post-treatment was comparable to placebo. Future research should define the safety and tolerability profile, including risk of C. difficile colitis and microbial antibiotic resistance, with repeated courses of rifaximin in patients with non-constipation-predominant irritable bowel syndrome (ClinicalTrials.gov: NCT00269412, NCT00731679, and NCT00724126). © 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Tolerability, safety, and efficacy of PEG 3350 as a 1-day bowel preparation in children.

PubMed

Walia, Ritu; Steffen, Rita; Feinberg, Lisa; Worley, Sarah; Mahajan, Lori

2013-02-01

The aim of the study was to evaluate the tolerability, safety, and efficacy of polyethylene glycol (PEG) 3350 without electrolytes as a 1-day bowel preparation for colonoscopy in children. A prospective study of 45 children undergoing colonoscopy prescribed PEG 3350 without electrolytes mixed with a commercial electrolyte beverage was performed. Patients <45 kg received 136 g of PEG 3350 without electrolytes mixed in 32 ounces of Gatorade. Patients ≥ 45 kg were given 255 g of PEG 3350 without electrolytes in 64 ounces of Gatorade A basic metabolic panel was performed at the time of the clinic visit and just before colonoscopy. Patients completed a survey related to bowel preparation. Endoscopists graded bowel preparation and noted the proximal extent of the examination. A total of 44 patients (14 ± 3 years) completed the study. One patient was excluded due to protocol breach. All subjects reported the preparation was easy (61%) or tolerable (39%). Adverse events included nausea (34%), abdominal pain (23%), vomiting (16%), abdominal distension (20%), bloating (23%), and dizziness (7%). Although significant changes in serum glucose and CO2 were noted, no therapeutic interventions were indicated. Significant changes in sodium, potassium chloride, blood urea nitrogen, or creatinine did not occur. Colonic preparation was rated as excellent in 23%, good in 52%, fair in 23%, and poor in 2% of patients. Intubation of the ileum was successful in 100%. One-day bowel preparation with high dose PEG 3350 mixed with commercial electrolyte solution is tolerable, safe, and effective in children before colonoscopy.

Clinical Pharmacokinetics and Pharmacodynamics of Safinamide.

PubMed

Müller, Thomas; Foley, Paul

2017-03-01

The symptoms of Parkinson's disease (PD) reflect disruptions of a number of brain neurotransmitter systems of varying type and degree. Pharmacological agents with multiple neurochemical mechanisms of action are therefore promising candidates for countering these problems and providing comprehensive symptomatic relief for patients. The pharmacological profile of safinamide includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent Na + channels, modulation of Ca 2+ channels, and inhibition of glutamate release. Safinamide is administered once daily at oral doses of 50-100 mg; it is well-tolerated and safe. Clinical trials have found that it ameliorates motor symptoms when added to established levodopa or single dopamine receptor agonist therapy. The future role of safinamide in PD may be that it enables a reduction in the dosage of dopamine replacement therapies, thereby reducing the adverse effects associated with these treatments. The clinical convenience (once-daily administration), safety, and tolerability of safinamide are better than those of dopamine receptor agonists. The introduction of safinamide reflects a change of approach to drug development for anti-parkinsonian agents in that its broad spectrum of action corresponds to the multiple heterogeneous alterations of brain neurochemistry in PD, rather than being targeted at a single receptor type or neurochemical process. Safinamide is a promising new instrument for the effective symptomatic therapy of PD.

A genetic algorithm based global search strategy for population pharmacokinetic/pharmacodynamic model selection

PubMed Central

Sale, Mark; Sherer, Eric A

2015-01-01

The current algorithm for selecting a population pharmacokinetic/pharmacodynamic model is based on the well-established forward addition/backward elimination method. A central strength of this approach is the opportunity for a modeller to continuously examine the data and postulate new hypotheses to explain observed biases. This algorithm has served the modelling community well, but the model selection process has essentially remained unchanged for the last 30 years. During this time, more robust approaches to model selection have been made feasible by new technology and dramatic increases in computation speed. We review these methods, with emphasis on genetic algorithm approaches and discuss the role these methods may play in population pharmacokinetic/pharmacodynamic model selection. PMID:23772792

Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.

PubMed

Sessa, Cristiana; Lorusso, Patricia; Tolcher, Anthony; Farace, Françoise; Lassau, Nathalie; Delmonte, Angelo; Braghetti, Antonio; Bahleda, Rastislav; Cohen, Patrick; Hospitel, Marie; Veyrat-Follet, Christine; Soria, Jean-Charles

2013-09-01

The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. ©2013 AACR.

Practical concept of pharmacokinetics/pharmacodynamics in the management of skin and soft tissue infections.

PubMed

Pea, Federico

2016-04-01

This article gives an overview of the practical concept of pharmacokinetic/pharmacodynamic principles useful for clinicians in the management of skin and soft tissue infections (SSTIs). Recent studies suggest that distinguishing between bacteriostatic or bactericidal activity when choosing an antimicrobial for the treatment of severe infections could probably be clinically irrelevant. Conversely, what could help clinicians in maximizing the therapeutic efficacy of the various drugs in routine practice is taking care of some pharmacokinetic/pharmacodynamic principles. Concentration-dependent agents may exhibit more rapid bacterial killing than observed with time-dependent agents. Serum concentrations may not always adequately predict tissue exposure in patients with SSTIs, and measuring concentrations at the infection site is preferable. Hydrophilic antimicrobials showed generally lower penetration rates than the lipophilic ones and might require alternative dosing approaches in the presence of severe sepsis or septic shock. Conversely, tissue penetration of lipophilic antimicrobials is often unaffected by the pathophysiological status. Real-time therapeutic drug monitoring may be a very helpful tool for optimizing therapy of severe infections. Taking care of pharmacokinetic/pharmacodynamic principles deriving from the most recent findings may help clinicians in maximizing treatment of SSTIs with antimicrobials in every situation.

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

PubMed Central

Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

2011-01-01

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119

Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949.

PubMed

Stalder, Anna K; Lott, Dominik; Strasser, Daniel S; Cruz, Hans G; Krause, Andreas; Groenen, Peter M A; Dingemanse, Jasper

2017-03-01

The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A 4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model. © 2016 The British Pharmacological Society.

Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease.

PubMed

Sandborn, W J; Elliott, D E; Weinstock, J; Summers, R W; Landry-Wheeler, A; Silver, N; Harnett, M D; Hanauer, S B

2013-08-01

Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461. © 2013 John Wiley & Sons Ltd.

Safety and tolerability of 13-valent pneumococcal conjugate vaccine in the elderly

PubMed Central

Durando, Paolo; Rosselli, Roberto; Cremonesi, Ilaria; Orsi, Andrea; Albanese, Erika; Barberis, Ilaria; Paganino, Chiara; Trucchi, Cecilia; Martini, Mariano; Marensi, Lorenzo; Turello, Valter; Study Group, the Ligurian Pneumococcal; Bregante, Alessandro; Cacciani, Roberto; Iudici, Rocco; La Marca, Diego; Pedano, Leonardo; Petrucci, Amadio Franco; Santolini, Maria; Sbisà, Valentina; Zacconi, Monica

2014-01-01

Background In September 2011 the European Medical Agency authorized the use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥50 years. The same occurred in the US in December 2011 when the Food and Drug Administration approved the use of PCV13 in the same target age-group with indication for the prevention of invasive pneumococcal diseases and community acquired pneumonia sustained by the serotypes contained in the vaccine. The Liguria Region, in Italy, implemented in 2013 an active and free of charge immunization strategy with PCV13 among adults affected by specific risk conditions and the elderly aged ≥70 years. Methods An observational study was performed in order to assess the safety and tolerability of PCV13 among elderly dwelling in the metropolitan area of Genoa, the capital city of Liguria Region. Eligible subjects, who received PCV13 following the public health immunization campaign at the Local Health Unit 3 of Genoa, provided a written informed consent to take part in the study. Eight-hundred-seventy-one subjects were enrolled between October 2013 and May 2014: all were monitored by qualified healthcare personnel for at least 30 min after vaccination at the outpatient clinics, in order to assess any possible sudden reaction. The occurrence of a series of local and systemic solicited reactions and of any unsolicited Adverse Events (AEs) was monitored using a self-administered clinical diary and by regular phone contacts up to 14 and 21 d following immunization, respectively. Moreover, a 6-months follow-up following vaccination was planned in order to monitor Severe Adverse Events (SAEs). Results No sudden reaction occurred in vaccinees at the outpatient clinics. Pain (27.4%) was the most frequent reaction reported by subjects at the injection site, while new muscle pain (13.6%), fatigue (10.7%), and headache (9.9%) resulted the most common systemic reactions. Rates of the main reactions reported in this on-field study resulted

Tolerance Signatures in Transplant Recipients

PubMed Central

Newell, Kenneth A.; Turka, Laurence A.

2015-01-01

Purpose of review The intent of this review is to describe biomarkers that predict or identify individuals who exhibit tolerance to a transplanted organ. The identification of tolerance biomarkers would spare some individuals the toxicity of immunosuppressive agents, enhance the safety of studies to induce tolerance, and provide insights into mechanisms of tolerance that may aid in designing new regimens. Recent findings Studies of tolerant kidney transplant recipients have revealed an association with B cells. More recent studies have suggested that these B cells may be less mature than from those in nontolerant recipients, and specially suited to suppress alloimmune responses. Biomarkers in tolerant liver transplant patients appear to be distinct from those associated renal tolerance. Most reports have identified an association with NK and/or γδ T cells rather than B cells. Recent data indicate biomarkers associated with iron homeostasis within the transplanted liver more accurately predict the tolerant state than do biomarkers expressed in the blood, suggesting that the renal allograft itself, which is infrequently sampled, would be informative. Summary Given the encouraging progress in identifying tolerance biomarkers, it will be important to validate these markers in larger studies of transplant recipients undergoing prospective minimization or withdrawal of immunosuppression. PMID:26107969

A safety and tolerability study of differently-charged nanoparticles for local pulmonary drug delivery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harush-Frenkel, Oshrat; Bivas-Benita, Maytal; Nassar, Taher

Nanoparticle (NP) based drug delivery systems provide promising opportunities in the treatment of lung diseases. Here we examined the safety and tolerability of pulmonary delivered NPs consisting of PEG-PLA as a function of particle surface charge. The rationale for such a comparison should be attributed to the differential pulmonary toxicity of positively and negatively charged PEG-PLA NP. Thus, the local and systemic effects of pulmonary administered NPs were investigated following 5 days of daily endotracheal instillation to BALB/c mice that were euthanized on the eighth or nineteenth day of the experiment. We collected bronchoalveolar lavages and studied hematological as wellmore » as histochemistry parameters. Notably, the cationic stearylamine based PEG-PLA NPs elicited increased local and systemic toxic effects both on the eighth and nineteenth day. In contrast, anionic NPs of similar size were much better tolerated with local inflammatory effects observed only on the eighth experimental day after pulmonary instillation. No systemic toxicity effect was observed although a moderate change was noted in the platelet count that was not considered to be of clinical significance. No pathological observations were detected in the internal organs following instillation of anionic NPs. Overall these observations suggest that anionic PEG-PLA NPs are useful pulmonary drug carriers that should be considered as a promising therapeutic drug delivery system.« less

Mathematical properties and parameter estimation for transit compartment pharmacodynamic models.

PubMed

Yates, James W T

2008-07-03

One feature of recent research in pharmacodynamic modelling has been the move towards more mechanistically based model structures. However, in all of these models there are common sub-systems, such as feedback loops and time-delays, whose properties and contribution to the model behaviour merit some mathematical analysis. In this paper a common pharmacodynamic model sub-structure is considered: the linear transit compartment. These models have a number of interesting properties as the length of the cascade chain is increased. In the limiting case a pure time-delay is achieved [Milsum, J.H., 1966. Biological Control Systems Analysis. McGraw-Hill Book Company, New York] and the initial behaviour becoming increasingly sensitive to parameter value perturbation. It is also shown that the modelled drug effect is attenuated, though the duration of action is longer. Through this analysis the range of behaviours that such models are capable of reproducing are characterised. The properties of these models and the experimental requirements are discussed in order to highlight how mathematical analysis prior to experimentation can enhance the utility of mathematical modelling.

Tolerability and safety of the intravenous immunoglobulin octagam® 10% in patients with immune thrombocytopenia: a post-authorisation safety analysis of two non-interventional phase IV trials.

PubMed

Wietek, Stefan; Svorc, Daniel; Debes, Anette; Svae, Tor-Einar

2018-05-01

To provide detailed data on the tolerability and safety of octagam ® 10%, a ready-to-use intravenous immunoglobulin, in a subgroup of patients with immune thrombocytopenia (ITP) involved in an integrated analysis of post-authorisation safety surveillance (PASS) studies. A subgroup analysis was conducted using data collected from two non-interventional studies that included patients with ITP treated with octagam ® 10%. Patients were observed and monitored for possible adverse drug reactions (ADRs) during or after administration of octagam ® 10%, with a particular focus on thromboembolic events (TEEs). ADRs were analysed at the case and event level. In this analysis of 112 patients receiving octagam ® 10% (mean dose 0.4 g/kg/infusion), there were five cases with at least one adverse drug reaction (ADR) associated with 626 infusions of octagam ® 10% (case incidence of 0.8% per infusion). ADRs were of mild or moderate severity. There were a total of 10 events, most commonly back pain (n = 3) and headache (n = 2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events involved drug exposure during pregnancy. There were no TEEs or other serious ADRs. In this subgroup analysis of patients who received octagam ® 10% (manufactured using an amended process) in two PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. No TEEs or other serious ADRs were reported. Routine clinical use of octagam ® 10% was safe and well tolerated, with no unexpected safety issues, in patients with ITP. The two studies from which data were taken are registered with the International Standard Randomised Controlled Trial Number Registry, numbers ISRCTN58800347 and ISRCTN02245668.

Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis.

PubMed

Ohba, Fuminori; Nomoto, Maiko; Hojo, Seiichiro; Akama, Hideto

2016-01-01

The purpose of the present studies was to assess the safety, tolerability and pharmacokinetics of topical application of a novel phosphodiesterase inhibitor, E6005, in healthy volunteers and in patients with atopic dermatitis (AD). In two randomized, investigator-blind, vehicle-controlled studies, we evaluated the topical application of E6005 ointment at concentrations ranging from 0.01% to 0.2% in healthy volunteers (Study 001) and in patients with AD (Study 101). Thirty-six subjects were enrolled in Study 001 and 40 in Study 101. Neither skin irritation nor photosensitization was observed with application of E6005 in Study 001. Four subjects receiving E6005 in Study 001 experienced a treatment-emergent adverse event (application site edema, increased alanine aminotransferase or erythema); three of these subjects discontinued the study. Two subjects receiving E6005 in Study 101 experienced an adverse event (gout or enterocolitis); one discontinued the study. Plasma concentrations of E6005 were below the limit of quantification (1 ng/ml) in both studies. E6005 ointment exhibited acceptable safety and tolerability. Topical application of E6005 ointment resulted in very low systemic exposure to E6005 in healthy volunteers and in patients with AD.

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

PubMed

Vormoor, B; Veal, G J; Griffin, M J; Boddy, A V; Irving, J; Minto, L; Case, M; Banerji, U; Swales, K E; Tall, J R; Moore, A S; Toguchi, M; Acton, G; Dyer, K; Schwab, C; Harrison, C J; Grainger, J D; Lancaster, D; Kearns, P; Hargrave, D; Vormoor, J

2017-06-01

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies. © 2016 Wiley Periodicals, Inc.

Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers.

PubMed

Blin, O; Jacquet, A; Callamand, S; Jouve, E; Habib, M; Gayraud, D; Durand, A; Bruguerolle, B; Pisano, P

1999-10-01

To describe the pharmacokinetic-pharmacodynamic modelling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers. This was a randomized double-blind, placebo-controlled two-way cross-over study. The effect of lorazepam was examined with the following tasks: choice reaction time, immediate and delayed cued recall of paired words and immediate and delayed free recall and recognition of pictures. The mean calculated EC50 values derived from the PK/PD modelling of the different tests ranged from 12.2 to 15.3 ng ml-1. On the basis of the statistical comparison of the EC50 values, the delayed recall trials seemed to be more impaired than the immediate recall trials; similar observations were made concerning the recognition vs recall tasks. The parameter values derived from PK/PD modelling, and especially the EC50 values, may provide sensitive indices that can be used, rather than the raw data derived from pharmacodynamic measurements, to compare CNS effects of benzodiazepines.

Hysterosalpingo-foam sonography (HyFoSy): Tolerability, safety and the occurrence of pregnancy post-procedure.

PubMed

Tanaka, Keisuke; Chua, Jackie; Cincotta, Robert; Ballard, Emma L; Duncombe, Gregory

2018-02-01

Fallopian tube patency testing is an essential part of infertility evaluation. Hysterosalpingo-contrast sonography (HyCoSy) has been described as reliable, well tolerated and safe compared to other modalities such as laparoscopy and a dye test or hysterosalpingography. Limited availability of the previously used contrast has led to the introduction of a foam contrast agent as an alternative. To assess the tolerability, safety and occurrence of pregnancy post-procedure of hysterosalpingo-foam sonography (HyFoSy). A retrospective cohort study of women who had a HyFoSy at Queensland Ultrasound for Women from March 2013 to February 2015. A questionnaire was sent to their referring doctor to identify any complications or subsequent pregnancies with or without artificial reproductive technology (ART) within six months of the HyFoSy. Of 200 women, four cases were abandoned due to difficulty introducing the intracervical catheter, severe discomfort or a vasovagal episode. Response from referring doctors for 155 women reported no post-procedural complication. One hundred and eleven women were followed up for at least six months. Twenty-four out of 59 women (40.7%) who had ART and 24 out of 52 women (46.2%) who did not have ART conceived. Fifty percent of women who were nulligravida at the time of investigation, found to have at least one patent fallopian tube, whose partner had a normal semen analysis, spontaneously conceived within the time of follow up. HyFoSy is well tolerated and safe. A preponderance of pregnancies in the first month after HyFoSy suggests that a therapeutic effect may exist. © 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

PubMed Central

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-01-01

Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. PMID:23016924

Safety and tolerance of a probiotic formula in early infancy comparing two probiotic agents: a pilot study.

PubMed

Weizman, Zvi; Alsheikh, Ahmed

2006-10-01

To compare the safety and tolerance of two formulas, supplemented with different probiotic agents, in early infancy. Prospective randomized placebo-controlled trial. Clinics of a University Medical Center. Full-term healthy infants aged less than 4 months. Infants were randomly assigned for 4 weeks to a standard milk-based formula supplemented with either Bifidobacterium lactis (BB-12), Lactobacillus reuteri (ATCC 55730) or a probiotics-free formula. Growth parameters, daily characteristics of feeding, stooling and behavior, and side effects. Fifty-nine infants, aged 3-65 days, were included. Subjects in all three groups were similar at entry in terms of gestational age, birth weight, sex, growth parameters and breast feeding rate prior to the study. The supplemented formulas were well accepted and did not reveal any adverse effects. A comparison of growth parameters, and variables of feeding, stooling and crying and irritability did not reveal any significant differences between groups. The use of formula supplemented with either Lactobacillus reuteri or Bifidobacterium lactis in early infancy, was safe, well tolerated and did not adversely affect growth, stooling habits or infant behavior.

[Efficacy, tolerability and safety of paliperidone extended-release in the treatment of schizophrenia and schizoaffective disorder].

PubMed

Bellantuono, Cesario; Santone, Giovanni

2012-01-01

The paper represents a systematic review on the efficacy, tolerability and safety of paliperidone, an antipsychotic drug recently approved in Italy for the treatment of schizophrenia and of schizoaffective disorder. A comprehensive PubMed search using the term "paliperidone" was performed from January 1980 to February 2011. Papers reporting data on efficacy in the treatment of schizophrenia and of schizoaffective disorder were included, also if published as abstracts and all retrieved articles were manually searched for other references of interest. Paliperidone was found to be effective in short and long-term treatment of schizophrenia, as well as in the treatment of schizoaffective disorder. For both disorders, paliperidone showed to be effective in improving psychotic and affective symptoms. In the studies analyzed it was well tolerated and the most frequent reported adverse events were mild extrapyramidal symptoms and an increase in serum prolactin levels. Paliperidone has been shown to be an effective and safe medication for the treatment of schizophrenia and schizoaffective disorder. Further controlled clinical trials are needed to confirm this clinical profile in the long-term treatment, as well as for specific conditions such as schizophrenic patients with medical comorbidities.

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers.

PubMed

Yassen, Ashraf; Olofsen, Erik; Romberg, Raymonda; Sarton, Elise; Danhof, Meindert; Dahan, Albert

2006-06-01

The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers. Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic-pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine's antinociceptive effect: (1) E(max) model with an effect compartment model, (2) "power" model with an effect compartment model, (3) receptor association-dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association-dissociation model with a linear transduction function. The latter pharmacokinetic-pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine's pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (k(eo)) was 0.00447 min(-1) (95% confidence interval, 0.00299-0.00595 min(-1)). The receptor dissociation rate constant (k(off)) was 0.0785 min(-1) (95% confidence interval, 0.0352-0.122 min(-1)), and k(on) was 0.0631 ml . ng(-1) . min(-1) (95% confidence interval, 0.0390-0.0872 ml . ng(-1) . min(-1)). This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

PubMed

Germovsek, Eva; Barker, Charlotte I S; Sharland, Mike; Standing, Joseph F

2018-04-19

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.

Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study.

PubMed

Pinter, M M; Pogarell, O; Oertel, W H

1999-04-01

Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance. Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings. There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%--resulting in 1.7 more hours "on" time a day--compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams. Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.

Safety, Tolerability, and Efficacy of Quetiapine in Youth with Schizophrenia or Bipolar I Disorder: A 26-Week, Open-Label, Continuation Study

PubMed Central

Pathak, Sanjeev; Earley, Willie R.; Liu, Sherry; DelBello, Melissa

2013-01-01

Abstract Objective The purpose of this study was to describe the safety, tolerability, and efficacy of quetiapine monotherapy continued for up to 26-weeks in youth with schizophrenia or bipolar I disorder. Methods Medically healthy boys and girls with a baseline Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) diagnosis of schizophrenia (ages 13–17 years) or a manic episode of bipolar I disorder (ages 10–17 years) who participated in one of two acute, double-blind, placebo-controlled studies of immediate-release quetiapine were potentially eligible to enroll in a 26-week, open-label study. During the open-label study, quetiapine was flexibly dosed at 400–800 mg/day, with options to reduce dosing to 200 mg/day based on tolerability. Safety and tolerability outcomes assessed from open-label baseline to week 26 included adverse events (AEs), metabolic/laboratory parameters, extrapyramidal symptoms, suicidality, and vital signs. Results Of 381 patients enrolled in the open-label study (n=176, schizophrenia; n=205, bipolar disorder diagnosis), 237 patients (62.2%) completed the 26-week study period (71.0%, schizophrenia; 54.6%, bipolar disorder). The most common AEs reported during the study included somnolence, headache, sedation, weight increase, and vomiting. A total of 14.9% of patients experienced a shift to potentially clinically significant low levels of high-density lipoprotein cholesterol and 10.2% of patients experienced a shift to potentially clinically significant high triglyceride levels. Weight gain ≥7% was reported in 35.6% of patients between open-label baseline and final visit. After adjustment for normal growth, 18.3% of study participants experienced clinically significant weight gain (i.e., increase in body mass index ≥0.5 standard deviations from baseline). Conclusions In this 26-week study, quetiapine flexibly dosed at 400–800 mg/day, with options to reduce dosing based on tolerability, was generally safe

Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial.

PubMed

Smilowitz, Jennifer T; Moya, Jackelyn; Breck, Melissa A; Cook, Chelsea; Fineberg, Annette; Angkustsiri, Kathleen; Underwood, Mark A

2017-05-30

Historically, bifidobacteria were the dominant intestinal bacteria in breastfed infants. Still abundant in infants in developing nations, levels of intestinal bifidobacteria are low among infants in developed nations. Recent studies have described an intimate relationship between human milk and a specific subspecies of Bifidobacterium, B. longum subsp. infantis (B. infantis), yet supplementation of breastfed, healthy, term infants with this organism, has not been reported. The IMPRINT Study, a Phase I clinical trial, was initiated to determine the safety and tolerability of supplementing breastfed infants with B. infantis (EVC001). Eighty mother-infant dyads were enrolled in either lactation support plus B. infantis supplementation (BiLS) or lactation support alone (LS). Starting with Day 7 postnatal, BiLS infants were fed 1.8-2.8 × 10 10  CFU B. infantis EVC001 daily in breast milk for 21 days. Mothers collected fecal samples, filled out health questionnaires, and kept daily logs about their infants' feeding and gastrointestinal symptoms from birth until Day 61 postnatal. Safety and tolerability were determined from maternal reports. There were no differences in the mean gestational age at birth, weight 1 and 2 months postnatal, and breast milk intake between groups. The mean Log 10 change in fecal Bifidobacterium from Day 6 to Day 28 was higher (p = 0.0002) for BiLS (6.6 ± 2.8 SD) than for LS infants (3.5 ± 3.5 SD). Daily stool number was higher (p < 0.005) for LS and lower (p < 0.05) for BiLS infants during supplementation than at Baseline. During supplementation, watery stools decreased and soft stools increased by 36% over baseline in BiLS infants (p < 0.05) with no significant changes in stool consistency for the LS infants. None of the safety and tolerability endpoints, including flatulence, bloody stool, body temperature, ratings of gastrointestinal symptoms, use of antibiotics or gas-relieving medications, infant colic, jaundice, number

Steady-state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients.

PubMed

Belldina, Eric B; Huang, Mei Y; Schneider, Jerry A; Brundage, Richard C; Tracy, Timothy S

2003-11-01

Cysteamine is used to reduce tissue cystine content in patients suffering from nephropathic cystinosis. The objectives of the current study were to investigate pharmacokinetics and pharmacodynamics of cysteamine bitartrate in children and young adults with nephropathic cystinosis. Cysteamine bitartrate was administered to 11 cystinosis patients at their regular dose level in a single-dose, open-label, steady-state study. Blood samples were collected and analysed for plasma cysteamine and white blood cell cystine content and pharmacokinetic and pharmacodynamic parameters estimated by NONMEM analysis using a linked pharmacokinetic-pharmacodynamic model. Cysteamine was rapidly cleared from the plasma (mean CL/F = 32.3 ml min(-1) kg(-1), range = 17.3-52.2), appeared to be extensively distributed (mean Vss/F = 15.1 l, range 2.7-32.3) and exhibited a mean Tmax of 1.4 h. White blood cell cystine content post-dosing was significantly decreased compared with pre- and post-dose values (average decrement approximately 47%). A counter-clockwise hysteresis was noted in all patients, suggestive of a lag time (mean Tlag = 0.44 h, range 0.22-0.92) between drug concentration and effect. The results of this study establish that cysteamine is rapidly cleared from the plasma but that an every 6 h dosing interval adequately maintains white blood cell cystine content below the target of 1 nmol cystine per mg protein.

Evaluating Pharmacokinetic and Pharmacodynamic Interactions with Computational Models in Cumulative Risk Assessment

EPA Science Inventory

Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture ...

Pharmacokinetics and pharmacodynamics of edivoxetine (LY2216684), a norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder.

PubMed

Kielbasa, William; Quinlan, Tonya; Jin, Ling; Xu, Wen; Lachno, D Richard; Dean, Robert A; Allen, Albert J

2012-08-01

Edivoxetine (LY2216684) is a selective and potent norepinephrine reuptake inhibitor (NERI). The pharmacokinetics (PK) and pharmacodynamics (PD) of edivoxetine were assessed in children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD) following single and once-daily oral doses of edivoxetine. During a phase 1 open-label safety, tolerability, and PK study, pediatric patients were administered edivoxetine at target doses of 0.05, 0.1, 0.2 and 0.3 mg/kg, and blood samples were collected to determine plasma concentrations of edivoxetine for PK assessments and plasma 3,4-dihydroxyphenylglycol (DHPG) concentrations for PD assessments. Edivoxetine plasma concentrations were measured using liquid chromatography with tandem mass spectrometric detection, and DHPG was measured using liquid chromatography with electrochemical detection. Edivoxetine PK was comparable between children and adolescents. The time to maximum concentration (t(max)) of edivoxetine was ∼2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t(1/2)) of ∼6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC(0-∞)) and maximum plasma concentration (C(max)) were observed, and there was no discernable difference in the apparent clearance (CL/F) or the apparent volume of distribution at steady state (V(ss)/F) across the dose range. In adolescents, edivoxetine caused a maximum decrease in plasma DHPG concentrations from baseline of ∼28%, most notably within 8 hours of edivoxetine administration. This initial study in pediatric patients with ADHD provides new information on the PK profile of edivoxetine, and exposures that decrease plasma DHPG consistent with the mechanism of action of a NERI. The PK and PD data inform edivoxetine pharmacology and can be used to develop comprehensive population PK and/or PK-PD models to guide dosing

Safety, Tolerability and Immunogenicity of Pentavalent Rotavirus Vaccine Manufactured by a Modified Process.

PubMed

Martinón-Torres, Federico; Greenberg, David; Varman, Meera; Killar, John A; Hille, Darcy; Strable, Erica L; Stek, Jon E; Kaplan, Susan S

2017-04-01

Rotavirus is the leading cause of severe diarrhea in infants and young children. The current formulation of pentavalent rotavirus vaccine (RV5) must be stored refrigerated at 2-8°C. A modified formulation of RV5 (RV5mp) has been developed with stability at 37°C for 7 days and an expiry extended to 36 months when stored at 2-8°C. This study (ClinicalTrials.gov identifier: NCT01600092; EudraCT number: 2012-001611-23) evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. To maintain blinding, both vaccine formulations were stored refrigerated at 2-8°C for the duration of the study. Immunogenicity endpoints were (1) serum neutralizing antibody titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and (2) proportion of subjects with a ≥3-fold rise from baseline for serum neutralizing antibody to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and serum antirotavirus immunoglobulin A. The RV5mp group (n = 505) and RV5 group (n = 509) had comparable safety profiles. There were no deaths and no vaccine-related serious adverse events in this study. With respect to immunogenicity, RV5mp was noninferior compared with RV5. Serum neutralizing antibody responses by country and breast-feeding status were generally consistent with the overall results. RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile of the currently licensed RV5. A vaccine that is stable at room temperature may be more convenient for vaccinators, particularly in places where the cold chain is unreliable, and ultimately will permit more widespread use.

Pharmacodynamic and pharmacokinetic assessment of pulmonary rehabilitation mixture for the treatment of pulmonary fibrosis.

PubMed

Zhao, Juanjuan; Ren, Yan; Qu, Yubei; Jiang, Wanglin; Lv, Changjun

2017-06-14

Pulmonary rehabilitation mixture (PRM), a Chinese herbal medicine formula, has been used to treat pulmonary fibrosis for decades. In this study, we systematically evaluated the pharmacodynamic and pharmacokinetic performance of PRM. The pharmacodynamic results showed that PRM could improve the condition of CoCl 2 -stimulated human type II alveolar epithelial cells, human pulmonary microvascular endothelial cells, human lung fibroblasts and pulmonary fibrosis rats induced by bleomycin, PRM treatment reduced the expression of platelet-derived growth factor, fibroblast growth factor, toll-like receptor 4, high-mobility group box protein 1 and hypoxia-inducible factor 1α. In the pharmacokinetic study, an accurate and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method was developed and validated for the simultaneous determination of calycosin, calycosin-7-O-glucoside, formononetin, ononin and mangiferin of PRM in the rat plasma for the first time. The method was then successfully applied to the comparative pharmacokinetic study of PRM in normal and pulmonary fibrosis rats. The five constituents could be absorbed in the blood after the oral administration of PRM and exhibited different pharmacokinetic behaviors in normal and pulmonary fibrosis rats. In summary, PRM exhibited a satisfactory pharmacodynamic and pharmacokinetic performance, which highlights PRM as a potential multi-target oral drug for the treatment of pulmonary fibrosis.

Effect of the CYP2C8 genotype on the pharmacokinetics and pharmacodynamics of repaglinide.

PubMed

Tomalik-Scharte, Dorota; Fuhr, Uwe; Hellmich, Martin; Frank, Dorothee; Doroshyenko, Oxana; Jetter, Alexander; Stingl, Julia C

2011-05-01

The pharmacokinetics of repaglinide shows pronounced interindividual variability, for which several reasons have been considered, including interactions with drugs inhibiting CYP2C8 and CYP2C8 genetic polymorphism. However, existing data on the role of genetic polymorphisms in repaglinide disposition are not fully consistent. We studied the effect of CYP2C8*3 on the pharmacokinetics and pharmacodynamics of repaglinide in 29 healthy whites carrying CYP2C8*3/*3 (n = 4), CYP2C8*1/*3 (n = 13), or CYP2C8*1/*1 (n = 12). After administration of a single dose of 2 mg of repaglinide, blood was drawn for assessment of repaglinide pharmacokinetics and pharmacodynamics, and urine was collected to quantify the main repaglinide metabolites M1 and M4 up to 24 h postdose. Repaglinide and the metabolites were quantified by liquid chromatography-tandem mass spectrometry. Considering only the effect of CYP2C8*3, the mean (95% confidence interval) area under the time-concentration curve (AUC) from zero to infinity of repaglinide was 72.4 (6.7-138.0), 97.2 (59.2-135.2), and 105.9 (52.4-159.3) ng · ml(-1) · h and the maximal concentration (C(max)) was 38.5 (3.8-73.2), 50.3 (37.5-63.0), and 60.3 (31.5-89.1) ng · ml(-1), respectively, in carriers of CYP2C8*3/*3, CYP2C8*1/*3, and CYP2C8*1/*1 [p > 0.05, one-way analysis of variance (ANOVA)]. In addition, for urinary metabolite excretion and pharmacodynamic parameters, i.e., mean and maximal changes in insulin and glucose concentration, no significant differences between CYP2C8 genotypes were observed. Likewise, no significant effects on the pharmacokinetics or pharmacodynamics were observed when AUC and C(max) of repaglinide were corrected for reported effects of the SLCO1B1 521T>C polymorphism or when both polymorphisms were tested in a two-way ANOVA. In conclusion, CYP2C8*3 does not seem to play an important role in the pharmacokinetics and pharmacodynamics of repaglinide given in a therapeutic dose.

Long-term efficacy, safety and tolerability of Remoxy for the management of chronic pain.

PubMed

Pergolizzi, Joseph V; Zampogna, Gianpietro; Taylor, Robert; Raffa, Robert B

2015-03-01

Historically, chronic pain generally went under-treated for a variety of objective and subjective reasons, including difficulty to objectively diagnose and manage over a long period of time, potential serious adverse effects of commonly available medications, and patient, healthcare and societal concerns over opioid medications. More recently, in an effort to redress the under-treatment of pain, the number of prescriptions of opioid analgesics has risen dramatically. However, paralleling the increased legitimate use has been a concomitant increase in opioid abuse, misuse and diversion. Pharmaceutical companies have responded by developing a variety of opioid formulations designed to deter abuse by making the products more difficult to tamper with. One such product is Remoxy(®), an extended-release formulation of the strong opioid oxycodone. We review the efficacy, safety and tolerability of this formulation based on the available published literature.

Enhancing value of clinical pharmacodynamics in oncology drug development: An alliance between quantitative pharmacology and translational science.

PubMed

Venkatakrishnan, K; Ecsedy, J A

2017-01-01

Clinical pharmacodynamic evaluation is a key component of the "pharmacologic audit trail" in oncology drug development. We posit that its value can and should be greatly enhanced via application of a robust quantitative pharmacology framework informed by biologically mechanistic considerations. Herein, we illustrate examples of intersectional blindspots across the disciplines of quantitative pharmacology and translational science and offer a roadmap aimed at enhancing the caliber of clinical pharmacodynamic research in the development of oncology therapeutics. © 2016 American Society for Clinical Pharmacology and Therapeutics.

29 CFR 1905.6 - Public notice of a granted variance, limitation, variation, tolerance, or exemption.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., tolerance, or exemption. 1905.6 Section 1905.6 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR RULES OF PRACTICE FOR VARIANCES, LIMITATIONS, VARIATIONS, TOLERANCES, AND EXEMPTIONS UNDER THE WILLIAMS-STEIGER OCCUPATIONAL SAFETY AND HEALTH ACT OF 1970...

On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprine or 6-mercaptopurine intolerant IBD patients

PubMed Central

de Boer, Nanne KH; Derijks, Luc JJ; Gilissen, Lennard PL; Hommes, Daniel W; Engels, Leopold GJB; de Boer, Sybrand Y; den Hartog, Gijsbertus; Hooymans, Piet M; Mäkelburg, Anja BU; Westerveld, Barend D; Naber, Anton HJ; Mulder, Chris JJ; de Jong, Dirk J

2005-01-01

AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year. METHODS: Database analysis. RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%) and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly. CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials. PMID:16222751

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study.

PubMed

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5-25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics.

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study

PubMed Central

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

Abstract This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5–25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics. PMID:26817604

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-05-01

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy.

PubMed

Ross, Ashley E; Hughes, Robert M; Glavaris, Stephanie; Ghabili, Kamyar; He, Ping; Anders, Nicole M; Harb, Rana; Tosoian, Jeffrey J; Marchionni, Luigi; Schaeffer, Edward M; Partin, Alan W; Allaf, Mohamad E; Bivalacqua, Trinity J; Chapman, Carolyn; O'Neal, Tanya; DeMarzo, Angelo M; Hurley, Paula J; Rudek, Michelle A; Antonarakis, Emmanuel S

2017-11-28

To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post-treatment at prostatectomy. We conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in men with high-risk localized prostate cancer undergoing radical prostatectomy. The primary endpoint was the proportion of patients in each arm who achieved at least a two-fold reduction in GLI1 mRNA expression in post-treatment versus pre-treatment tumor tissue. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety. Fourteen men were equally randomized (7 per arm) to either neoadjuvant Sonidegib or observation for 4 weeks prior to prostatectomy. Six of seven men (86%) in the Sonidegib arm (and none in the control group) achieved a GLI1 suppression of at least two-fold. In the Sonidegib arm, drug was detectable in plasma and in prostatic tissue; and median intra-patient GLI1 expression decreased by 63-fold, indicating potent suppression of Hedgehog signaling. Sonidegib was well tolerated, without any Grade 3-4 adverse events observed. Disease-free survival was comparable among the two arms (HR = 1.50, 95% CI 0.26-8.69, P = 0.65). Hedgehog pathway activity (as measured by GLI1 expression) was detectable at baseline in men with localized high-risk prostate cancer. Sonidegib penetrated into prostatic tissue and induced a >60-fold suppression of the Hedgehog pathway. The oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.

A Phase II, Randomized, Double-Blind Clinical Study Evaluating the Safety, Tolerability, and Efficacy of a Topical Minocycline Foam, FMX103, for the Treatment of Facial Papulopustular Rosacea.

PubMed

Mrowietz, Ulrich; Kedem, Tal Hetzroni; Keynan, Rita; Eini, Meir; Tamarkin, Dov; Rom, Dror; Shirvan, Mitchell

2018-06-01

Our objective was to demonstrate the safety, tolerability, and efficacy of a minocycline foam, FMX103, in the treatment of moderate-to-severe facial papulopustular rosacea. This was a phase II, randomized, double-blind, multicenter study. Healthy subjects aged ≥ 18 years with moderate-to-severe rosacea that had been diagnosed ≥ 6 months previously and with ≥ 12 inflammatory facial lesions were randomized (1:1:1) to receive once-daily 1.5% FMX103, 3% FMX103, or vehicle for 12 weeks. The primary endpoint was the absolute change in inflammatory lesion count at week 12. Other assessments included grade 2 or higher Investigator's Global Assessment (IGA) improvement, IGA "clear" or "almost clear" (IGA 0/1), clinical erythema, and safety/tolerability. Safety and efficacy were evaluated at weeks 2, 4, 8, and 12, with a safety follow-up at week 16. A total of 232 subjects were randomized; 213 completed the study. At week 12, inflammatory lesion count reduction was significantly greater for the 1.5 and 3% FMX103 doses than for vehicle (21.1 and 19.1 vs. 7.8, respectively; both p < 0.001). Both doses were significantly better than vehicle for achieving grade 2 or higher IGA improvement and assessment of "clear" or "almost clear." Both doses appeared generally safe and well tolerated. In total, 11 (4.7%) subjects reported treatment-related treatment-emergent adverse events (TEAEs); all but one (eye discharge) were dermal related, and all resolved by study end. No treatment-related systemic TEAEs were reported. Four subjects discontinued the study because of TEAEs (3% FMX103, n = 3; vehicle, n = 1). Topical minocycline foam, FMX103, appeared to be an effective, safe, and well tolerated treatment for moderate-to-severe papulopustular rosacea. These results support further investigation in larger clinical trials. CLINICALTRIALS. NCT02601963.

Influence of obstructive jaundice on pharmacodynamics of rocuronium.

PubMed

Wang, Zhen-Meng; Zhang, Peng; Lin, Mi-Jia; Tan, Bo; Qiu, Hai-Bo; Yu, Wei-Feng

2013-01-01

Anesthetics are variable in patients with obstructive jaundice. The minimum alveolar concentration awake of desflurane is reduced in patients with obstructive jaundice, while it has no effect on pharmacodynamics and pharmacokinetics of propofol. In this study, we investigated the influence of obstructive jaundice on the pharmacodynamics and blood concentration of rocuronium. Included in this study were 26 control patients and 27 patients with obstructive jaundice. Neuromuscular block of rocuronium was monitored by acceleromyography. Onset time, spontaneous recovery of the height of twitch first (T1) to 25% of the final T1 value (Duration 25%, Dur 25%), recovery index (RI), and spontaneous recovery of train-of-four (TOF) ratios to 70% were measured. The plasma rocuronium concentrations were determined by high performance liquid chromatography using berberine as an internal standard. There was no significant difference in onset time between the two groups. The Dur 25%, the recovery index and the time of recovery of the TOF ratios to 70% were all prolonged in the obstructive jaundice group compared with the control group. The plasma concentration of rocuronium at 60, 90 and 120 min after bolus administration was significantly higher in the obstructive jaundice group. The neuromuscular blockade by rocuronium is prolonged in obstructive jaundice patients, and therefore precautions should be taken in case of postoperative residual neuromuscular block. The possible reason is impedance of rocuronium excretion due to biliary obstruction and increased plasma unbound rocuronium because of free bilirubin competing with it for albumin binding.

Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

PubMed Central

Lew, Kim H.; Ludwig, Elizabeth A.; Milad, Mark A.; Donovan, Kathleen; Middleton, Elliott; Ferry, James J.; Jusko, William J.

2014-01-01

The pharmacokinetics and selected pharmacodynamic responses to methylprednisolone were investigated in six men and six premenopausal women after a dose of 0.6 mg/kg ideal body weight. Women (luteal phase) exhibited a greater methylprednisolone clearance (0.45 versus 0.29 L/hr/kg) and shorter elimination half-life (1.7 versus 2.6 hours) than men. The volume of distribution of methylprednisolone was similar when normalized for ideal body weight. Pharmacodynamic models were used to examine the methylprednisolone suppressive effects on cortisol secretion and basophil and helper T lymphocyte trafficking. A significantly smaller 50% inhibitory concentration (IC50) value (0.1 versus 1.7 ng/ml) was seen in the women for suppression of cortisol secretion, indicating increased sensitivity. However, the area under the concentration-time curve of effect was similar for both groups. The IC50 values for effects of methylprednisolone on basophil trafficking related to estradiol concentrations in a log-linear fashion in women, with increased sensitivity found at higher estradiol concentrations. Men displayed a greater 24-hour net suppression in blood basophil numbers, but no difference was observed in net cortisol and helper T lymphocyte suppression between the sexes. These findings suggest that methylprednisolone dosages should be based on ideal body weight. Although women are more sensitive to methylprednisolone as measured by cortisol suppression, they eliminate the drug more quickly, generally producing a similar net response. PMID:8222483

Safety, tolerability, and pharmacokinetics of sumatriptan suppositories following single and multiple doses in healthy volunteers.

PubMed

Kunka, R L; Hussey, E K; Shaw, S; Warner, P; Aubert, B; Richard, I; Fowler, P A; Pakes, G E

1997-06-01

A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite

Clinical pharmacokinetic and pharmacodynamic profile of lacosamide.

PubMed

Cawello, Willi

2015-09-01

Lacosamide-a third-generation antiepileptic drug available in multiple formulations-was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. In 2014, lacosamide was approved as monotherapy for POS by the US Food and Drug Administration (FDA). A loading dose administration was approved in 2013 by the European Medicines Agency and in 2014 by the FDA. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing and reduction in long-term channel availability without affecting physiological function. Lacosamide is rapidly absorbed, with maximum plasma concentrations reached 0.5-4 h after intake. Oral bioavailability is high (100 %) for a dose up to 800 mg. Bioavailability is irrespective of food intake. Variability in pharmacokinetic parameters is low (coefficients of variation almost all <20 %). The pharmacokinetic profile of lacosamide is consistent in healthy subjects and across different patient populations studied. Lacosamide elimination from plasma occurs with a terminal half-life of approximately 13 h in young subjects and 14-16 h in elderly subjects; this difference does not impact the dose regimen. Lacosamide produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for reduction of seizure frequency can be described by a maximum effect (E max) model. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, has low protein binding of less than 15 % and, because it has multiple elimination pathways, it has no clinically relevant interactions with commonly prescribed medications.

Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo.

PubMed

Malizia, A L; Gunn, R N; Wilson, S J; Waters, S H; Bloomfield, P M; Cunningham, V J; Nutt, D J

1996-01-01

To date, the study of the relationship between drug occupancy and action in the brain has had to rely on the use of either animal models or of indirect kinetic measures in man, e.g. serum concentrations of unbound drug (as a measure of "free" drug in brain). We describe the first set of experiments which directly measure agonist-induced changes in both pharmacodynamic effects and pharmacokinetic parameters simultaneously and which demonstrate the feasibility of these studies in man. Five healthy volunteers each had two PET scans using [11C]flumazenil (a radiolabelled benzodiazepine site antagonist) as part of a study investigating kinetic models and the relationship between occupancy and effect of benzodiazepine site ligands. In both studies the [11C]flumazenil was displaced from the brain by infusion of midazolam administered i.v. 30 min into the scan. In one study a higher dose of midazolam was administered than in the other (range 12.5-50 micrograms/kg). Time-activity curves of the concentration of radioligand were derived in 17 different brain regions using a stereotactic automatic method of region selection. We demonstrated that there are significant differences in an index of occupancy, induced by the two different doses of midazolam, both across brain regions and within subjects. There was a significant correlation between measured occupancy index change and pharmacodynamic effects as measured by the peak change in beta 1 spectral power on EEG. There was no significant correlation between dose administered and EEG changes; plasma concentrations of midazolam were correlated with the occupancy index and with the EEG measures. In addition, we have demonstrated that a non-regional total index of brain occupancy can be obtained by analysing the non-tomographic data obtained with the PET scanner (total radioactivity counts head curve) and that this index shows significant correlations both with the dose administered and with the pharmacodynamic measure. This last

Sex Differences in Pharmacokinetics and Pharmacodynamics

PubMed Central

Soldin, OP; Mattison, DR

2013-01-01

Males and females differ in their response to drug treatment. These differences can be critical in response to drug treatment. It is therefore essential to understand those differences to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. We summarize the sex differences that impact pharmacokinetics and pharmacodynamics and include a general comparison of clinical pharmacology as it applies to men, pregnant and non-pregnant women. Since this is an area rapidly evolving, it is essential for the practitioner to review drug prescribing information and recent literature to understand fully the impact of sex differences in clinical therapeutics. PMID:19385708

Pharmacodynamic analysis of ceftriaxone, gatifloxacin,and levofloxacin against Streptococcus pneumoniae with the use of Monte Carlo simulation.

PubMed

Frei, Christopher R; Burgess, David S

2005-09-01

To evaluate the pharmacodynamics of four intravenous antimicrobial regimens-ceftriaxone 1 g, gatifloxacin 400 mg, levofloxacin 500 mg, and levofloxacin 750 mg, each every 24 hours-against recent Streptococcus pneumoniae isolates. Pharmacodynamic analysis using Monte Carlo simulation. The Surveillance Network (TSN) 2002 database. Streptococcus pneumoniae isolates (7866 isolates) were stratified according to penicillin susceptibilities as follows: susceptible (4593), intermediate (1986), and resistant (1287). Risk analysis software was used to simulate 10,000 patients by integrating published pharmacokinetic parameters, their variability, and minimum inhibitory concentration (MIC) distributions from the TSN database. Probability of target attainment was determined for percentage of time above the MIC (%T > MIC) from 0-100% for ceftriaxone and area under the concentration-time curve (AUC):MIC ratio from 0-150 for the fluoroquinolones. For ceftriaxone, probability of target attainment remained 90% or greater against the three isolate groups until a %T > MIC of 70% or greater, and it remained 90% or greater against susceptible and intermediate isolates over the entire interval (%T > MIC 0-100%). For levofloxacin 500 mg, probability of target attainment was 90% at an AUC:MIC < or = 30, but the curve declined sharply with further increases in pharmacodynamic target. Levofloxacin 750 mg achieved a probability of target attainment of 99% at an AUC:MIC ratio < or = 30; the probability remained approximately 90% until a target of 70 or greater, when it declined steeply. Gatifloxacin demonstrated a high probability (99%) of target attainment at an AUC:MIC ratio < or = 30, and it remained above 90% until a target of 70. Ceftriaxone maintained high probability of target attainment over a broad range of pharmacodynamic targets regardless of penicillin susceptibility (%T > MIC 0-60%). Levofloxacin 500 mg maintained high probability of target attainment for AUC:MIC ratios 0

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

PubMed

Siproudhis, L; Jones, D; Shing, R Ng Kwet; Walker, D; Scholefield, J H

2014-03-01

Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. This is the first randomised controlled study to investigate the efficacy

48 CFR 822.304 - Variations, tolerances, and exemptions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... and Safety Standards Act 822.304 Variations, tolerances, and exemptions. When issuing a contract for nursing home care, a contracting officer may exempt a contractor from certain requirements of the Contract Work Hours and Safety Standards Act (40 U.S.C. 3701-3708) regarding the payment of overtime (see 29 CFR...

48 CFR 822.304 - Variations, tolerances, and exemptions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... and Safety Standards Act 822.304 Variations, tolerances, and exemptions. When issuing a contract for nursing home care, a contracting officer may exempt a contractor from certain requirements of the Contract Work Hours and Safety Standards Act (40 U.S.C. 3701-3708) regarding the payment of overtime (see 29 CFR...

Translating Pharmacokinetic and Pharmacodynamic Data into Practice.

PubMed

Visser, Marike

2018-05-01

Pharmacokinetic (PK) and pharmacodynamic (PD) publications provide scientific evidence for incorporation in evidence-based veterinary medicine, aiding the clinician in selecting doses and dosing intervals. PK and PD studies have reported wide variations within exotic species, due to physiologic differences in absorption, distribution, metabolism, and excretion. PK studies offer species-specific data to help tailor doses and dosing routes to individual patients, minimize toxicity, and provide a cornerstone for PD studies to determine drug efficacy. This article reviews the application of PK parameters and the challenges in determining the PD activity of drugs, with a particular emphasis on exotic species. Copyright © 2018 Elsevier Inc. All rights reserved.

Pharmacokinetic and pharmacodynamic characterization of a new formulation containing synergistic proportions of interferons alpha-2b and gamma (HeberPAG®) in patients with mycosis fungoides: an open-label trial

PubMed Central

2012-01-01

Background The synergistic combination of interferon (IFN) alpha-2b and IFN gamma results in more potent in vitro biological effects mediated by both IFNs. The aim of this investigation was to evaluate by first time the pharmacokinetics and pharmacodynamics of this combination in patients with mycosis fungoides. Methods An exploratory, prospective, open-label clinical trial was conducted. Twelve patients, both genders, 18 to 75 years-old, with mycosis fungoides at stages IB to III, were eligible for the study. All of them received intramuscularly a single high dose (23 × 106 IU) of a novel synergistic IFN mixture (HeberPAG®) for pharmacokinetic and pharmacodynamic studies. Serum IFN alpha-2b and IFN gamma concentrations were measured during 96 hours by commercial enzyme immunoassays (EIA) specific for each IFN. Other blood IFN-inducible markers and laboratory variables were used as pharmacodynamics and safety criteria. Results The pharmacokinetic evaluation by EIA yielded a similar pattern for both IFNs that are also in agreement with the well-known described profiles for these molecules when these are administered separately. The average values for main parameters were: Cmax: 263 and 9.3 pg/mL; Tmax: 9.5 and 6.9 h; AUC: 4483 and 87.5 pg.h/mL, half-life (t1/2): 4.9 and 13.4 h; mean residence time (MRT): 13.9 and 13.5 h, for serum IFN alpha-2b and IFN gamma, respectively. The pharmacodynamic variables were strongly stimulated by simultaneous administration of both IFNs: serum neopterin and beta-2 microglobulin levels (β2M), and stimulation of 2’-5’ oligoadenylate synthetase (OAS1) mRNA expression. The most encouraging data was the high increment of serum neopterin, 8.0 ng/mL at 48 h, not been described before for any unmodified or pegylated IFN. Additionally, β2M concentration doubled the pre-dose value at 24–48 hours. For both variables the values remained clearly upper baseline levels at 96 hours. Conclusions HeberPAG®possesses improved

An escalating dose study to assess the safety, tolerability and immunogenicity of a Herpes Simplex Virus DNA vaccine, COR-1.

PubMed

Dutton, Julie L; Woo, Wai-Ping; Chandra, Janin; Xu, Yan; Li, Bo; Finlayson, Neil; Griffin, Paul; Frazer, Ian H

2016-12-01

This paper describes a single site, open-label Phase I clinical trial evaluating the safety, tolerability and immunogenicity in healthy volunteers of a herpes simplex polynucleotide vaccine that has previously been shown to enhance immunogenicity and protect against lethal herpes simplex virus type 2 (HSV-2) challenge in mice. Five escalating doses of the vaccine, COR-1, were given by intradermal injection to HSV-1 and 2 seronegative healthy individuals. COR-1 was found to be safe and well-tolerated; the only vaccine-related adverse events were mild. While vaccine-induced antibody responses were not detectable, cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study, and local inflammation at the immunisation site was observed. This study indicates COR-1 has potential to be used as a therapeutic vaccine for HSV-2 infection.

Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC.

PubMed

Zhang, Hongjie; Garcia, Jose M

2015-06-01

Cancer anorexia-cachexia syndrome (CACS) is associated with increased morbidity and mortality. Anamorelin is a novel, orally active ghrelin receptor agonist in clinical development for the treatment of CACS in NSCLC. The aim of this review is to summarize preclinical and clinical studies evaluating anamorelin as a potential promising treatment for CACS in NSCLC. Pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability of anamorelin for the treatment of CACS in NSCLC were reviewed. Anamorelin administration may lead to increases in food intake, body weight and lean body mass, and a stimulatory effect on growth hormone secretion in NSCLC patients. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. Targeting ghrelin receptors presents the advantage of potentially addressing multiple mechanisms of CACS simultaneously including appetite, muscle protein balance, adipose tissue metabolism, energy expenditure and inflammation. Clinical data suggest that anamorelin is well tolerated and it effectively increases appetite, body weight and lean mass in patients with advanced NSCLC. Long-term safety remains unknown at this time. The potential synergistic effects of anamorelin with nutritional support or exercise as well as its efficacy/safety in other tumor types are also unknown.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus.

PubMed

Goday, A; Bellido, D; Sajoux, I; Crujeiras, A B; Burguera, B; García-Luna, P P; Oleaga, A; Moreno, B; Casanueva, F F

2016-09-19

Brackground:The safety and tolerability of very low-calorie-ketogenic (VLCK) diets are a current concern in the treatment of obese type 2 diabetes mellitus (T2DM) patients. Evaluating the short-term safety and tolerability of a VLCK diet (<50 g of carbohydrate daily) in an interventional weight loss program including lifestyle and behavioral modification support (Diaprokal Method) in subjects with T2DM. Eighty-nine men and women, aged between 30 and 65 years, with T2DM and body mass index between 30 and 35 kg m(-)(2) participated in this prospective, open-label, multi-centric randomized clinical trial with a duration of 4 months. Forty-five subjects were randomly assigned to the interventional weight loss (VLCK diet), and 44 to the standard low-calorie diet. No significant differences in the laboratory safety parameters were found between the two study groups. Changes in the urine albumin-to-creatinine ratio in VLCK diet were not significant and were comparable to control group. Creatinine and blood urea nitrogen did not change significantly relative to baseline nor between groups. Weight loss and reduction in waist circumference in the VLCK diet group were significantly larger than in control subjects (both P<0.001). The decline in HbA1c and glycemic control was larger in the VLCK diet group (P<0.05). No serious adverse events were reported and mild AE in the VLCK diet group declined at last follow-up. The interventional weight loss program based on a VLCK diet is most effective in reducing body weight and improvement of glycemic control than a standard hypocaloric diet with safety and good tolerance for T2DM patients.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus

PubMed Central

Goday, A; Bellido, D; Sajoux, I; Crujeiras, A B; Burguera, B; García-Luna, P P; Oleaga, A; Moreno, B; Casanueva, F F

2016-01-01

Brackground: The safety and tolerability of very low-calorie-ketogenic (VLCK) diets are a current concern in the treatment of obese type 2 diabetes mellitus (T2DM) patients. Objective: Evaluating the short-term safety and tolerability of a VLCK diet (<50 g of carbohydrate daily) in an interventional weight loss program including lifestyle and behavioral modification support (Diaprokal Method) in subjects with T2DM. Methods: Eighty-nine men and women, aged between 30 and 65 years, with T2DM and body mass index between 30 and 35 kg m−2 participated in this prospective, open-label, multi-centric randomized clinical trial with a duration of 4 months. Forty-five subjects were randomly assigned to the interventional weight loss (VLCK diet), and 44 to the standard low-calorie diet. Results: No significant differences in the laboratory safety parameters were found between the two study groups. Changes in the urine albumin-to-creatinine ratio in VLCK diet were not significant and were comparable to control group. Creatinine and blood urea nitrogen did not change significantly relative to baseline nor between groups. Weight loss and reduction in waist circumference in the VLCK diet group were significantly larger than in control subjects (both P<0.001). The decline in HbA1c and glycemic control was larger in the VLCK diet group (P<0.05). No serious adverse events were reported and mild AE in the VLCK diet group declined at last follow-up. Conclusions: The interventional weight loss program based on a VLCK diet is most effective in reducing body weight and improvement of glycemic control than a standard hypocaloric diet with safety and good tolerance for T2DM patients. PMID:27643725

Safety and tolerability of prescription omega-3 fatty acids: A systematic review and meta-analysis of randomized controlled trials.

PubMed

Chang, Cheng-Ho; Tseng, Ping-Tao; Chen, Nai-Yu; Lin, Pei-Chin; Lin, Pao-Yen; Chang, Jane Pei-Chen; Kuo, Feng-Yu; Lin, Jenshinn; Wu, Ming-Chang; Su, Kuan-Pin

2018-02-01

Omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] are widely recommended for health promotion. Over the last decade, prescription omega-3 fatty acid products (RxOME3FAs) have been approved for medical indications. Nonetheless, there is no comprehensive analysis of safety and tolerability of RxOME3FAs so far. A systematic review of randomized controlled trials (RCTs) was carried out based on searches in six electronic databases. The studies involving marketed RxOME3FA products were included, and adverse-effect data were extracted for meta-analysis. Subgroup analysis and meta-regression were conducted to explore the sources of potential heterogeneity. Among the 21 included RCTs (total 24,460 participants; 12,750 from RxOME3FA treatment cohort and 11,710 from control cohort), there was no definite evidence of any RxOME3FA-emerging serious adverse event. Compared with the control group, RxOME3FAs were associated with more treatment-related dysgeusia (fishy taste; p = 0.011) and skin abnormalities (eruption, itching, exanthema, or eczema; p < 0.001). Besides, RxOME3FAs had mild adverse effects upon some non-lipid laboratory measurements [elevated fasting blood sugar (p = 0.005); elevated alanine transaminase (p = 0.022); elevated blood urea nitrogen (p = 0.047); decreased hemoglobin (p = 0.002); decreased hematocrit (p = 0.009)]. Subgroup analysis revealed that EPA/DHA combination products were associated with more treatment-related gastrointestinal adverse events [eructation (belching; p = 0.010); nausea (p = 0.044)] and low-density lipoprotein cholesterol elevation (p = 0.009; difference in means = 4.106mg/dL). RxOME3FAs are generally safe and well tolerated but not free of adverse effects. Post-marketing surveillance and observational studies are still necessary to identify long-term adverse effects and to confirm the safety and tolerability profiles of RxOME3FAs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pharmacodynamic evaluation of self micro-emulsifying formulation of standardized extract of Lagerstroemia speciosa for antidiabetic activity.

PubMed

Agarwal, Vipin Kumar; Amresh, Gupta; Chandra, Phool

Lagerstroemia speciosa (SEL) leaves are a popular folk medicine for diabetes treatment due to presence of corosolic acid. It has low water solubility resulting poor absorption after oral administration. Self micro-emulsified drug delivery system is the way by which we can improve the oral absorption of drug. The objective of this study was to develop the self micro-emulsifying formulation of standardized extract of SEL leaves and evaluate its pharmacodynamic performance for antidiabetic activity. The SME formulation was prepared by using sefsol-218 as oil, cremophor-EL as surfactant and transcutol-P as co-surfactant. The ratio of surfactant and co-surfactant was determined by pseudoternary phase diagram. SME formulations were characterized for dilution at different pH, self emulsification, optical clarity, globule size and thermodynamic stability. Pharmacodynamic evaluation of formulations was assessed in Wistar rats by using parameters viz. blood glucose level and serum lipid profile. SEL loaded SME formulation was successfully developed by using sefsol-218, cremophor-EL and transcutol-P with a droplet size 23.53 nm. Pharmacodynamic results showed a higher reduction in blood glucose by SME formulation than SEL without SMES respectively at 50 mg/kg dose while reduction produced at dose of 100 mg/kg was found significant and better on 15th day of study. The percentage reduction produced by SME formulation on serum lipid profile was also significant and was more prominent than SEL. This study confirms that the formulation elevates the pharmacodynamic performance of SEL approximately two fold. Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

Development of an integrated semi-automated system for in vitro pharmacodynamic modelling.

PubMed

Wang, Liangsu; Wismer, Michael K; Racine, Fred; Conway, Donald; Giacobbe, Robert A; Berejnaia, Olga; Kath, Gary S

2008-11-01

The aim of this study was to develop an integrated system for in vitro pharmacodynamic modelling of antimicrobials with greater flexibility, easier control and better accuracy than existing in vitro models. Custom-made bottle caps, fittings, valve controllers and a modified bench-top shaking incubator were used. A temperature-controlled automated sample collector was built. Computer software was developed to manage experiments and to control the entire system including solenoid pinch valves, peristaltic pumps and the sample collector. The system was validated by pharmacokinetic simulations of linezolid 600 mg infusion. The antibacterial effect of linezolid against multiple Staphylococcus aureus strains was also studied in this system. An integrated semi-automated bench-top system was built and validated. The temperature-controlled automated sample collector allowed unattended collection and temporary storage of samples. The system software reduced the labour necessary for many tasks and also improved the timing accuracy for performing simultaneous actions in multiple parallel experiments. The system was able to simulate human pharmacokinetics of linezolid 600 mg intravenous infusion accurately. A pharmacodynamic study of linezolid against multiple S. aureus strains with a range of MICs showed that the required 24 h free drug AUC/MIC ratio was approximately 30 in order to keep the organism counts at the same level as their initial inoculum and was about > or = 68 in order to achieve > 2 log(10) cfu/mL reduction in the in vitro model. The integrated semi-automated bench-top system provided the ability to overcome many of the drawbacks of existing in vitro models. It can be used for various simple or complicated pharmacokinetic/pharmacodynamic studies efficiently and conveniently.

Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide

PubMed Central

Abel, Samantha; Nichols, Donald J; Brearley, Christopher J; Eve, Malcolm D

2000-01-01

Aims The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Methods Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 μg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1–2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. Results Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml−1 increase in plasma dofetilide concentration produced a 17–19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. Conclusions These results suggest that cimetidine increased dofetilide exposure by inhibiting renal

In Vitro Pharmacodynamics of AZD5206 against Staphylococcus aureus

PubMed Central

Chang, Kai-Tai; Yang, Zhen; Newman, Joseph; Hu, Ming

2013-01-01

AZD5206 is a novel antimicrobial agent with potent in vitro activity against Staphylococcus aureus. We evaluated the in vitro pharmacodynamics of AZD5206 against a standard wild-type methicillin-susceptible strain (ATCC 29213) and a clinical strain of methicillin-resistant S. aureus (SA62). Overall, bacterial killing against a low baseline inoculum was more remarkable. Low dosing exposures and/or high baseline inoculum resulted in early reduction in bacterial burden, followed by regrowth and selective amplification of the resistant population. PMID:23229481

Influence of Obstructive Jaundice on Pharmacodynamics of Rocuronium

PubMed Central

Lin, Mi-Jia; Tan, Bo; Qiu, Hai-Bo; Yu, Wei-Feng

2013-01-01

Background Anesthetics are variable in patients with obstructive jaundice. The minimum alveolar concentration awake of desflurane is reduced in patients with obstructive jaundice, while it has no effect on pharmacodynamics and pharmacokinetics of propofol. In this study, we investigated the influence of obstructive jaundice on the pharmacodynamics and blood concentration of rocuronium. Methods Included in this study were 26 control patients and 27 patients with obstructive jaundice. Neuromuscular block of rocuronium was monitored by acceleromyography. Onset time, spontaneous recovery of the height of twitch first (T1) to 25% of the final T1 value (Duration 25%, Dur 25%), recovery index (RI), and spontaneous recovery of train-of-four (TOF) ratios to 70% were measured. The plasma rocuronium concentrations were determined by high performance liquid chromatography using berberine as an internal standard. Results There was no significant difference in onset time between the two groups. The Dur 25%, the recovery index and the time of recovery of the TOF ratios to 70% were all prolonged in the obstructive jaundice group compared with the control group. The plasma concentration of rocuronium at 60, 90 and 120 min after bolus administration was significantly higher in the obstructive jaundice group. Conclusions The neuromuscular blockade by rocuronium is prolonged in obstructive jaundice patients, and therefore precautions should be taken in case of postoperative residual neuromuscular block. The possible reason is impedance of rocuronium excretion due to biliary obstruction and increased plasma unbound rocuronium because of free bilirubin competing with it for albumin binding. PMID:24147111

Software safety

NASA Technical Reports Server (NTRS)

Leveson, Nancy

1987-01-01

Software safety and its relationship to other qualities are discussed. It is shown that standard reliability and fault tolerance techniques will not solve the safety problem for the present. A new attitude requires: looking at what you do NOT want software to do along with what you want it to do; and assuming things will go wrong. New procedures and changes to entire software development process are necessary: special software safety analysis techniques are needed; and design techniques, especially eliminating complexity, can be very helpful.

Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection.

PubMed

Nell, Andre S; D'lom, Eva; Bouic, Patrick; Sabaté, Montserrat; Bosser, Ramon; Picas, Jordi; Amat, Mercè; Churchyard, Gavin; Cardona, Pere-Joan

2014-01-01

To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection. Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV-) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/-): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV- status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation. This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future trials, preceded by an extended safety clinical

Safety, Tolerability, and Immunogenicity of the Novel Antituberculous Vaccine RUTI: Randomized, Placebo-Controlled Phase II Clinical Trial in Patients with Latent Tuberculosis Infection

PubMed Central

Nell, Andre S.; D’lom, Eva; Bouic, Patrick; Sabaté, Montserrat; Bosser, Ramon; Picas, Jordi; Amat, Mercè; Churchyard, Gavin; Cardona, Pere-Joan

2014-01-01

Objectives To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection. Methods and Findings Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV−) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/−): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV− status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation. Conclusion This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future

Politicas de tolerancia cero (Zero Tolerance Policies). ERIC Digest.

ERIC Educational Resources Information Center

McAndrews, Tobin

State legislatures and school boards are adopting a growing number of zero-tolerance polices toward weapons, guns, and violence. Zero-tolerance polices are rules intended to address specific school-safety issues. They have arisen in part as a response to the threat of the withdrawal of federal funds under the 1994 Gun-Free Schools Act, and…

Biotherapeutics in non-clinical development: Strengthening the interface between safety, pharmacokinetics-pharmacodynamics and manufacturing.

PubMed

Ulrich, Peter; Blaich, Guenter; Baumann, Andreas; Fagg, Rajni; Hey, Adam; Kiessling, Andrea; Kronenberg, Sven; Lindecrona, Rikke Hvid; Mohl, Silke; Richter, Wolfgang F; Tibbitts, Jay; Crameri, Flavio; Weir, Lucinda

2018-04-01

Biological drugs comprise a wide field of different modalities with respect to structure, pharmacokinetics and pharmacological function. Considerable non-clinical experience in the development of proteins (e.g. insulin) and antibodies has been accumulated over the past thirty years. In order to improve the efficacy and the safety of these biotherapeutics, Fc modifications (e.g. Fc silent antibody versions), combinations (antibody-drug conjugates, protein-nanoparticle combinations), and new constructs (darpins, fynomers) have been introduced. In the last decade, advanced therapy medicinal products (ATMPs) in research and development have become a considerable and strongly growing part of the biotherapeutic portfolio. ATMPs consisting of gene and cell therapy modalities or even combinations of them, further expand the level of complexity, which already exists in non-clinical development strategies for biological drugs and has thereby led to a further diversification of expertise in safety and PKPD assessment of biological drugs. It is the fundamental rationale of the BioSafe meetings, held yearly in the EU and in the US, to convene experts on a regular basis and foster knowledge exchange and mutual understanding in this fast growing area. In order to reflect at least partially the variety of the biotherapeutics field, the 2016 EU BioSafe meeting addressed the following topics in six sessions: (i) In vitro Meets in vivo to Leverage Biologics Development (ii) New developments and regulatory considerations in the cell and gene therapy field (iii) CMC Challenges with Biologics development (iv) Minipigs in non-clinical safety assessment (v) Opportunities of PKPD Assessment in Less Common Administration Routes In the breakout sessions the following questions were discussed: (i) Cynomolgus monkey as a reprotoxicology Species: Impact of Immunomodulators on Early Pregnancy Maintenance (ii) Safety Risk of Inflammation and Autoimmunity Induced by Immunomodulators (iii

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

Pharmacokinetic and Pharmacodynamic Comparison of Sildenafil‐Bosentan and Sildenafil‐Ambrisentan Combination Therapies for Pulmonary Hypertension

PubMed Central

Hakamata, A; Miyakawa, S; Irisawa, H; Takeuchi, K; Inui, N; Tanaka, S; Uchida, S; Watanabe, H

2016-01-01

To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4–5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration–time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime. PMID:26756977

Long-term safety and tolerability of once-daily mesalamine granules in the maintenance of remission of ulcerative colitis.

PubMed

Lichtenstein, Gary R; Barrett, Andrew C; Bortey, Enoch; Paterson, Craig; Forbes, William P

2014-08-01

Ulcerative colitis (UC), a chronic, relapsing, and remitting inflammatory bowel disease, requires long-term treatment to maintain remission. In this study, the long-term safety and tolerability of mesalamine granules (MG) therapy was evaluated in the maintenance of UC remission. Previous prospective studies evaluating different oral mesalamine formulations have not exceeded a duration of 14 months. A phase 3, multicenter, 24-month, open-label extension study evaluating MG 1.5 g once daily in patients who achieved previous remission from mild to moderate UC was performed. Eligible patients had successfully participated in 1 of 2 previous 6-month double-blind, placebo-controlled trials or were new patients in remission. Safety assessments included monitoring of adverse events (AEs) and clinical laboratory tests. Risk of UC recurrence was assessed by the occurrence of UC-related AEs. Of the 393 patients enrolled (280 from the double-blind studies; 113 new patients), 388 were included in the safety population. The most common AEs included nasopharyngitis (13.9%), headache (11.6%), and diarrhea (10.8%), and the incidence of these events was generally lower in the MG group versus historical placebo group from the double-blind studies. Pancreatic, renal, and hepatic AEs occurred in 23 patients (5.9%). The risk of UC-related AEs was low and was maintained for 24 months during the open-label study. Once-daily MG has a favorable safety profile for the maintenance of remission for up to 2 years in patients with UC.

Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies.

PubMed

Ponce, Rafael; Abad, Leslie; Amaravadi, Lakshmi; Gelzleichter, Thomas; Gore, Elizabeth; Green, James; Gupta, Shalini; Herzyk, Danuta; Hurst, Christopher; Ivens, Inge A; Kawabata, Thomas; Maier, Curtis; Mounho, Barbara; Rup, Bonita; Shankar, Gopi; Smith, Holly; Thomas, Peter; Wierda, Dan

2009-07-01

An evaluation of potential antibody formation to biologic therapeutics during the course of nonclinical safety studies and its impact on the toxicity profile is expected under current regulatory guidance and is accepted standard practice. However, approaches for incorporating this information in the interpretation of nonclinical safety studies are not clearly established. Described here are the immunological basis of anti-drug antibody formation to biopharmaceuticals (immunogenicity) in laboratory animals, and approaches for generating and interpreting immunogenicity data from nonclinical safety studies of biotechnology-derived therapeutics to support their progression to clinical evaluation. We subscribe that immunogenicity testing strategies should be adapted to the specific needs of each therapeutic development program, and data generated from such analyses should be integrated with available clinical and anatomic pathology, pharmacokinetic, and pharmacodynamic data to properly interpret nonclinical studies.

Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn's disease: a pilot study.

PubMed

Smith, Jill P; Field, Douglas; Bingaman, Sandra I; Evans, Robert; Mauger, David T

2013-04-01

There is an unmet need for safe and effective medicines to treat children with Crohn's disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells. The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn's disease. A pilot clinical trial was conducted in children with moderate to severe Crohn's disease. Fourteen subjects with a mean age of 12.3 years (range, 8 to 17 y) were enrolled. Children were randomized to placebo or naltrexone (0.1 mg/kg) orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and Quality of life was monitored by the Impact III survey. Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn's disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9) (P=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score ≤10) and 67% had improved with mild disease activity (decrease in PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (P=0.035). Naltrexone therapy seems safe with limited toxicity when given to children with Crohn's disease and may reduce disease activity.

Pharmacokinetic/Pharmacodynamic-Driven Drug Development

PubMed Central

Gallo, James M.

2010-01-01

The drug discovery and development enterprise, traditionally an industrial juggernaut, has spanned into the academic arena that is partially motivated by the National Institutes of Health Roadmap highlighting translational science and medicine. Since drug discovery and development represents a pipeline of basic to clinical investigations it meshes well with the prime “bench to the bedside” directive of translational medicine. The renewed interest in drug discovery and develpoment in academia provides an opportunity to rethink the hiearchary of studies with the hope to improve the staid approaches that have been critizied for lacking innovation. One area that has received limited attention concerns the use of pharmacokinetic [PK] and pharmacodynamic [PD] studies in the drug development process. Using anticancer drug development as a focus, this review will address past and current deficencies in how PK/PD studies are conducted and offer new strategies that might bridge the gap between preclinical and clinical trials. PMID:20687184

Damage Tolerance Assessment Branch

NASA Technical Reports Server (NTRS)

Walker, James L.

2013-01-01

The Damage Tolerance Assessment Branch evaluates the ability of a structure to perform reliably throughout its service life in the presence of a defect, crack, or other form of damage. Such assessment is fundamental to the use of structural materials and requires an integral blend of materials engineering, fracture testing and analysis, and nondestructive evaluation. The vision of the Branch is to increase the safety of manned space flight by improving the fracture control and the associated nondestructive evaluation processes through development and application of standards, guidelines, advanced test and analytical methods. The Branch also strives to assist and solve non-aerospace related NDE and damage tolerance problems, providing consultation, prototyping and inspection services.

Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution compared with prior prostaglandin therapy

PubMed Central

Henry, J Charles; Peace, James H; Stewart, Jeanette A; Stewart, William C

2008-01-01

Purpose To evaluate the efficacy, safety and tolerability of changing to travoprost BAK-free from prior prostaglandin therapy in patients with primary open-angle glaucoma or ocular hypertension. Design Prospective, multi-center, historical control study. Methods Patients treated with latanoprost or bimatoprost who needed alternative therapy due to tolerability issues were enrolled. Patients were surveyed using the Ocular Surface Disease Index (OSDI) to evaluate OSD symptoms prior to changing to travoprost BAK-free dosed once every evening. Patients were re-evaluated 3 months later. Results In 691 patients, travoprost BAK-free demonstrated improved mean OSDI scores compared to either latanoprost or bimatoprost (p < 0.0001). Patients having any baseline OSD symptoms (n = 235) demonstrated significant improvement after switching to travoprost BAK-free (p < 0.0001). In 70.2% of these patients, symptoms were reduced in severity by at least 1 level. After changing medications to travoprost BAK-free, mean intraocular pressure (IOP) was significantly decreased (p < 0.0001). Overall, 72.4% preferred travoprost BAK-free (p < 0.0001, travoprost BAK-free vs prior therapy). Travoprost BAK-free demonstrated less conjunctival hyperemia than either prior therapy (p < 0.0001). Conclusions Patients previously treated with a BAK-preserved prostaglandin analog who are changed to travoprost BAK-free have clinically and statistically significant improvement in their OSD symptoms, decreased hyperemia, and equal or better IOP control. PMID:19668762

Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis

PubMed Central

Box, Helen; Livermore, Joanne; Johnson, Adam; McEntee, Laura; Felton, Timothy W.; Whalley, Sarah; Goodwin, Joanne

2015-01-01

Isavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamic in vitro model of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates of Aspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively. PMID:26503648

Pharmacokinetics and pharmacodynamics of sofosbuvir and ledipasvir for the treatment of hepatitis C.

PubMed

Cuenca-Lopez, Francisca; Rivero, Antonio; Rivero-Juárez, Antonio

2017-01-01

The sofosbuvir (SOF) plus ledipasvir (LDV) fixed dose combination is the first direct action antiviral (DAA) single-treatment regimen (STR) to be commercialized. It is approved for the treatment of Hepatitis C virus (HCV) genotypes 1,3,4,5 and 6. Following approval in 2014, new pharmacokinetics and pharmacodynamics data were reported, which led to important clinical applications. Areas covered: This article reviews the pharmacokinetic and pharmacodynamic properties of the SOF/LDV fixed dose combination for the treatment of HCV. The topics covered include data regarding the drug´s absorption, distribution, metabolism and excretion and antiviral activity strategies such as the clinical dose selection and treatment duration. Expert opinion: The SOF/LDV fixed dose combination has good pharmacological properties that lead to a high sustained virological response after 12 or 24 weeks of treatment; there is minimal interference with other drugs or associated renal or hepatic impairment, such that dose adjustment is not necessary.

Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study.

PubMed

Burge, D J; Eisenman, J; Byrnes-Blake, K; Smolak, P; Lau, K; Cohen, S B; Kivitz, A J; Levin, R; Martin, R W; Sherrer, Y; Posada, J A

2017-07-01

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

Modeling of recovery profiles in mentally disabled and intact patients after sevoflurane anesthesia; a pharmacodynamic analysis.

PubMed

Shin, Teo Jeon; Noh, Gyu-Jeong; Koo, Yong-Seo; Han, Dong Woo

2014-11-01

Mentally disabled patients show different recovery profiles compared to normal patients after general anesthesia. However, the relationship of dose-recovery profiles of mentally disabled patients has never been compared to that of normal patients. Twenty patients (10 mentally disabled patients and 10 mentally intact patients) scheduled to dental surgery under general anesthesia was recruited. Sevoflurane was administered to maintain anesthesia during dental treatment. At the end of the surgery, sevoflurane was discontinued. End-tidal sevoflurane and recovery of consciousness (ROC) were recorded after sevoflurane discontinuation. The pharmacodynamic relation between the probability of ROC and end-tidal sevoflurane concentration was analyzed using NONMEM software (version VII). End-tidal sevoflurane concentration associated with 50% probability of ROC (C₅₀) and γ value were lower in the mentally disabled patients (C₅₀=0.37 vol %, γ=16.5 in mentally intact patients, C₅₀=0.19 vol %, γ=4.58 in mentally disabled patients). Mentality was a significant covariate of C₅₀ for ROC and γ value to pharmacodynamic model. A sigmoid Emanx model explains the pharmacodynamic relationship between end-tidal sevoflurane concentration and ROC. Mentally disabled patients may recover slower from anesthesia at lower sevoflurane concentration at ROC an compared to normal patients.

Modeling of Recovery Profiles in Mentally Disabled and Intact Patients after Sevoflurane Anesthesia; A Pharmacodynamic Analysis

PubMed Central

Shin, Teo Jeon; Noh, Gyu-Jeong; Koo, Yong-Seo

2014-01-01

Purpose Mentally disabled patients show different recovery profiles compared to normal patients after general anesthesia. However, the relationship of dose-recovery profiles of mentally disabled patients has never been compared to that of normal patients. Materials and Methods Twenty patients (10 mentally disabled patients and 10 mentally intact patients) scheduled to dental surgery under general anesthesia was recruited. Sevoflurane was administered to maintain anesthesia during dental treatment. At the end of the surgery, sevoflurane was discontinued. End-tidal sevoflurane and recovery of consciousness (ROC) were recorded after sevoflurane discontinuation. The pharmacodynamic relation between the probability of ROC and end-tidal sevoflurane concentration was analyzed using NONMEM software (version VII). Results End-tidal sevoflurane concentration associated with 50% probability of ROC (C50) and γ value were lower in the mentally disabled patients (C50=0.37 vol %, γ=16.5 in mentally intact patients, C50=0.19 vol %, γ=4.58 in mentally disabled patients). Mentality was a significant covariate of C50 for ROC and γ value to pharmacodynamic model. Conclusion A sigmoid Emanx model explains the pharmacodynamic relationship between end-tidal sevoflurane concentration and ROC. Mentally disabled patients may recover slower from anesthesia at lower sevoflurane concentration at ROC an compared to normal patients. PMID:25323901

49 CFR 325.9 - Measurement tolerances.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false Measurement tolerances. 325.9 Section 325.9 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY... allowed to take into account the effects of the following factors: (1) The consensus standard practice of...

Safety and Tolerability of Transitioning from Cangrelor to Ticagrelor in Patients Who Underwent Percutaneous Coronary Intervention.

PubMed

Badreldin, Hisham A; Carter, Danielle; Cook, Bryan M; Qamar, Arman; Vaduganathan, Muthiah; Bhatt, Deepak L

2017-08-01

The 3 phase 3 CHAMPION (Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials collectively demonstrated the safety of transitioning from cangrelor, a potent, parenteral rapidly-acting P2Y 12 inhibitor, to clopidogrel in patients who underwent percutaneous coronary intervention (PCI). However, variation in timing of therapy, site-specific binding, and drug half-lives may theoretically complicate switching to other oral P2Y 12 inhibitors. Since regulatory approval, limited data are available regarding the "real-world" safety and tolerability of transitioning to these more potent oral P2Y 12 antagonists. From November 2015 to January 2017, we evaluated the clinical profiles and efficacy and safety outcomes in cangrelor-treated patients who underwent PCI transitioned to clopidogrel (n = 42) or ticagrelor (n = 82) at a large, tertiary care center. Most patients receiving cangrelor underwent PCI with a drug-eluting stent for acute coronary syndrome via a radial approach in the background of unfractionated heparin. Stent thrombosis within 48 hours was rare and occurred in 1 patient treated with ticagrelor. Global Use of Strategies to Open Occluded Coronary Arteries-defined bleeding occurred in 20% of patients switched to ticagrelor and 29% of patients switched to clopidogrel, but none were severe or life-threatening. In conclusion, rates of stent thrombosis and severe/life-threatening bleeding were low and comparable with those identified in the CHAMPION program, despite use of more potent oral P2Y 12 inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

Population pharmacokinetic–pharmacodynamic analysis for sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade

PubMed Central

Kleijn, Huub J; Zollinger, Daniel P; van den Heuvel, Michiel W; Kerbusch, Thomas

2011-01-01

AIMS An integrated population pharmacokinetic–pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic–pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time. METHODS Data (n = 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects. RESULTS Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg−1 3 min after rocuronium, sugammadex 4 mg kg−1 during deep neuromuscular blockade and sugammadex 2 mg kg−1 during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time. CONCLUSIONS Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min. PMID:21535448

Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years.

PubMed

Schmader, Kenneth E; Levin, Myron J; Gnann, John W; McNeil, Shelly A; Vesikari, Timo; Betts, Robert F; Keay, Susan; Stek, Jon E; Bundick, Nickoya D; Su, Shu-Chih; Zhao, Yanli; Li, Xiaoming; Chan, Ivan S F; Annunziato, Paula W; Parrino, Janie

2012-04-01

Herpes zoster (HZ) adversely affects individuals aged 50-59, but vaccine efficacy has not been assessed in this population. This study was designed to determine the efficacy, safety, and tolerability of zoster vaccine for preventing HZ in persons aged 50-59 years. This was a randomized, double-blind, placebo-controlled study of 22 439 subjects aged 50-59 years conducted in North America and Europe. Subjects were given 1 dose of licensed zoster vaccine (ZV) (Zostavax; Merck) and followed for occurrence of HZ for ≥1 year (mean, 1.3 years) postvaccination until accrual of ≥96 confirmed HZ cases (as determined by testing lesions swabs for varicella zoster virus DNA by polymerase chain reaction). Subjects were followed for all adverse events (AEs) from day 1 to day 42 postvaccination and for serious AEs (SAEs) through day 182 postvaccination. The ZV reduced the incidence of HZ (30 cases in vaccine group, 1.99/1000 person-years vs 99 cases in placebo group, 6.57/1000 person-years). Vaccine efficacy for preventing HZ was 69.8% (95% confidence interval, 54.1-80.6). AEs were reported by 72.8% of subjects in the ZV group and 41.5% in the placebo group, with the difference primarily due to higher rates of injection-site AEs and headache. The proportion of subjects reporting SAEs occurring within 42 days postvaccination (ZV, 0.6%; placebo, 0.5%) and 182 days postvaccination (ZV, 2.1%; placebo, 1.9%) was similar between groups. In subjects aged 50-59 years, the ZV significantly reduced the incidence of HZ and was well tolerated. NCT00534248.

Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

PubMed Central

Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

2015-01-01

Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors

PubMed Central

Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A.; Raynaud, Florence I.; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S.; Kaye, Stan B.; Derynck, Mika K.; Workman, Paul; de Bono, Johann S.

2014-01-01

Purpose This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics, pharmacodynamics and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent and selective inhibitor of the Class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450mg once-daily, initially on days 1-21 every 28 days and later, utilizing continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma and tumor tissue. Results Pictilisib was well-tolerated. The most common toxicities were grade 1-2 nausea, rash and fatigue while the DLT was grade 3 maculopapular rash (450mg, 2 of 3 patients; 330mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in platelet rich plasma at 3 hours post-dose at the MTD and in tumor at pictilisib doses associated with AUC >20uM.hr. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100mg and signs of antitumor activity. The recommended Phase II dose was continuous dosing at 330mg once-daily. PMID:25370471

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PubMed

Sarker, Debashis; Ang, Joo Ern; Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A; Raynaud, Florence I; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S; Kaye, Stan B; Derynck, Mika K; Workman, Paul; de Bono, Johann S

2015-01-01

This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. ©2014 American Association for Cancer Research.

Bowel cleansing before colonoscopy: Balancing efficacy, safety, cost and patient tolerance

PubMed Central

Harrison, Nicole M; Hjelkrem, Michael C

2016-01-01

Effective colorectal cancer screening relies on reliable colonoscopy findings which are themselves dependent on adequate bowel cleansing. Research has consistently demonstrated that inadequate bowel preparation adversely affects the adenoma detection rate and leads gastroenterologists to recommend earlier follow up than is consistent with published guidelines. Poor preparation affects as many as 30% of colonoscopies and contributes to an increased cost of colonoscopies. Patient tolerability is strongly affected by the preparation chosen and manner in which it is administered. Poor tolerability is, in turn, associated with lower quality bowel preparations. Recently, several new developments in both agents being used for bowel preparation and in the timing of administration have brought endoscopists closer to achieving the goal of effective, reliable, safe, and tolerable regimens. Historically, large volume preparations given in a single dose were administered to patients in order to achieve adequate bowel cleansing. These were poorly tolerated, and the unpleasant taste of and significant side effects produced by these large volume regimens contributed significantly to patients’ inability to reliably complete the preparation and to a reluctance to repeat the procedure. Smaller volumes, including preparations that are administered as tablets to be consumed with water, given as split doses have significantly improved both the patient experience and efficacy, and an appreciation of the importance of the preparation to colonoscopy interval have produced additional cleansing. PMID:26788258

Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

PubMed

Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

2017-06-01

Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study.

PubMed

Pandey, Swaroop Kumar; Biswas, Subhasish; Gunjan, Sarika; Chauhan, Bhavana Singh; Singh, Sunil Kumar; Srivastava, Kumkum; Singh, Sarika; Batra, Sanjay; Tripathi, Renu

2016-09-01

Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development.

Efficacy, tolerance and safety of new intragastric air-filled balloon (Heliosphere BAG) for obesity: the experience of 17 cases.

PubMed

Trande, Paolo; Mussetto, Alessandro; Mirante, Vincenzo G; De Martinis, Elvira; Olivetti, Giampiero; Conigliaro, Rita L; De Micheli, Enrico A

2010-09-01

Overweight and obesity lead to serious health consequences, so that many strategies were recommended for preventing or curing this emerging problem. Treatments are various: diet, physical activity, psychotherapy, drugs, and bariatric surgery. Moreover, during these years, the use of intragastric balloon (BIB) to treat obesity increased rapidly, aimed to (1) reduce bariatric surgical risks; (2) reduce general surgical risks; (3) lead to a significant reduction in the prevalence of cardiovascular diseases, diabetes, musculoskeletal disorders and some cancers. Recently, a new device inflated with air to reduce weight has been developed since 2004 (Heliosphere BAG). Between March 2006 and September 2006, in our unit, intragastric air-filled balloon insertion was performed under general anesthesia and endoscopic control. The balloons were removed after 6 months. We evaluated efficacy, tolerance, and safety of this technique. Seventeen patients (eight men, nine women), with a mean age of 43 +/- 10 years (range 18-65), mean basal BMI of 46 +/- 8 (range 35-58) were included, after providing informed consent. Weight and BMI loss were evaluated in all patients. BMI decreased 4 +/- 3 (range +0.33/-11), weight loss was 11 +/- 9 kg (range +1/-29.5; 8.5%). 14/17 patients maintain a BMI > 35 at the time of balloon removal. The difference between initial weight and BMI was statistically significant (p = 0.02 for weight and p < 0.01 for BMI, T Student test). Tolerance was very good, limited only to some dyspeptic symptoms during the first 3 days after insertion. One asymptomatic gastric ulcer was seen at the removal of balloon. Only one severe adverse effect was registered at the time of insertion (acute coronary syndrome in patient with chronic coronary disease). No serious technical problems were noted at balloon insertion. Balloon removal was more difficult and successful in 15/17 cases (one distal migration and one patient led to surgery because of balloon fragmentation

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease.

PubMed

Farlow, Martin R; Grossberg, George T; Sadowsky, Carl H; Meng, Xiangyi; Velting, Drew M

2015-01-01

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.

Mechanisms of food processing and storage-related stress tolerance in Clostridium botulinum.

PubMed

Dahlsten, Elias; Lindström, Miia; Korkeala, Hannu

2015-05-01

Vegetative cultures of Clostridium botulinum produce the extremely potent botulinum neurotoxin, and may jeopardize the safety of foods unless sufficient measures to prevent growth are applied. Minimal food processing relies on combinations of mild treatments, primarily to avoid deterioration of the sensory qualities of the food. Tolerance of C. botulinum to minimal food processing is well characterized. However, data on effects of successive treatments on robustness towards further processing is lacking. Developments in genetic manipulation tools and the availability of annotated genomes have allowed identification of genetic mechanisms involved in stress tolerance of C. botulinum. Most studies focused on low temperature, and the importance of various regulatory mechanisms in cold tolerance of C. botulinum has been demonstrated. Furthermore, novel roles in cold tolerance were shown for metabolic pathways under the control of these regulators. A role for secondary oxidative stress in tolerance to extreme temperatures has been proposed. Additionally, genetic mechanisms related to tolerance to heat, low pH, and high salinity have been characterized. Data on genetic stress-related mechanisms of psychrotrophic Group II C. botulinum strains are scarce; these mechanisms are of interest for food safety research and should thus be investigated. This minireview encompasses the importance of C. botulinum as a food safety hazard and its central physiological characteristics related to food-processing and storage-related stress. Special attention is given to recent findings considering genetic mechanisms C. botulinum utilizes in detecting and countering these adverse conditions. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Effective concentration-based serum pharmacodynamics for antifungal azoles in a murine model of disseminated Candida albicans infection.

PubMed

Maki, Katsuyuki; Kaneko, Shuji

2013-12-01

An assessment of the effective in vivo concentrations of antifungal drugs is important in determining their pharmacodynamics, and therefore, their optimal dosage regimen. Here we establish the effective in vivo concentration-based pharmacodynamics of three azole antifungal drugs (fluconazole, itraconazole, and ketoconazole) in a murine model of disseminated Candida albicans infection. A key feature of this study was the use of a measure of mycelial (m) growth rather than of yeast growth, and pooled mouse sera rather than synthetic media as a growth medium, for determining the minimum inhibitory concentrations (MICs) of azoles for C. albicans (denoted serum mMICs). The serum mMIC assay was then used to measure antifungal concentrations and effects as serum antifungal titers in the serum of treated mice. Both serum mMIC and sub-mMIC values reflected the effective in vivo serum concentrations. Supra-mMIC and mMIC effects exhibited equivalent efficacies and were concentration-independent, while the sub-mMIC effect was concentration-dependent. Following administration of the minimum drug dosage that inhibited an increase in mouse kidney fungal burden, the duration periods of these effects were similar for all drugs tested. The average duration of either the mMIC effect including the supra-mMIC effect, the sub-mMIC effect, or the post-antifungal effect (PAFE) were 6.9, 6.5 and 10.6 h, respectively. Our study suggests that the area under the curve for serum drug concentration versus time, between the serum mMIC and the sub-mMIC, and exposure time above the serum sub-mMIC after the mMIC effect, are major pharmacodynamic parameters. These findings have important implications for effective concentration-based pharmacodynamics of fungal infections treated with azoles.

Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects.

PubMed

Nasveld, Peter E; Edstein, Michael D; Reid, Mark; Brennan, Leonard; Harris, Ivor E; Kitchener, Scott J; Leggat, Peter A; Pickford, Philip; Kerr, Caron; Ohrt, Colin; Prescott, William

2010-02-01

This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.

Randomized, Double-Blind Study of the Safety, Tolerability, and Efficacy of Tafenoquine versus Mefloquine for Malaria Prophylaxis in Nonimmune Subjects▿

PubMed Central

Nasveld, Peter E.; Edstein, Michael D.; Reid, Mark; Brennan, Leonard; Harris, Ivor E.; Kitchener, Scott J.; Leggat, Peter A.; Pickford, Philip; Kerr, Caron; Ohrt, Colin; Prescott, William

2010-01-01

This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis. PMID:19995933

Novel Δ9-tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

PubMed Central

Klumpers, Linda E; Beumer, Tim L; van Hasselt, Johan G C; Lipplaa, Astrid; Karger, Lennard B; Kleinloog, H Daniël; Freijer, Jan I; de Kam, Marieke L; van Gerven, Joop M A

2012-01-01

AIMS Among the main disadvantages of currently available Δ9-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®. METHODS This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed. RESULTS Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t1/2 was 72–80 min, tmax was 39–56 min and Cmax 2.92–4.69 ng ml−1. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min–1, 95% CI 2.7, 6.5). Namisol® was well tolerated. CONCLUSIONS Oral Namisol® showed promising PK and PD characteristics. Variability and tmax of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations. PMID:22680341

Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poon, Kirsten Achilles, E-mail: achilles.kirsten@gene.com; Flagella, Kelly; Beyer, Joseph

2013-12-01

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeysmore » and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (∼ 4400 μg DM1/m{sup 2}) and 30 mg/kg (∼ 6000 μg DM1/m{sup 2}) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m{sup 2}). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. - Highlights: • T-DM1 was well tolerated in preclinical studies in rats and cynomolgus monkeys. • T-DM1 is associated with bone marrow/hematologic, hepatic, and neuronal toxicities. • T-DM1 toxicities are related to DM1 mechanisms of action and

Pharmacokinetics and pharmacodynamics of smoked heroin.

PubMed

Jenkins, A J; Keenan, R M; Henningfield, J E; Cone, E J

1994-10-01

Despite the current popularity of smoking as a route of drug self-administration, there have been few human studies characterizing the pharmacokinetics and pharmacodynamics of smoked drugs of abuse. A variety of technological difficulties are encountered in the design of smoking studies, such as delivering reproducible doses and limiting the amount of pyrolysis of parent drug. As part of a concerted research effort to deliver precise, smoked doses of drug, a computer-assisted smoking device was utilized that delivered single puffs of heroin vapor to human subjects under controlled clinical conditions. Recovery studies indicated that the smoking device delivered approximately 89% of parent heroin to subjects. Although only two qualified heroin smokers could be identified as eligible volunteers, their participation provided the unique opportunity to study the pharmacokinetics and pharmacodynamics of smoked heroin. The two subjects were administered four smoked heroin doses in ascending order. In addition, four intravenous doses of heroin were administered for comparison of effects and estimation of bioavailability. Concurrent physiological, behavioral, and performance measures were collected along with blood samples. Blood was analyzed for heroin, 6-acetylmorphine, and morphine by solid-phase extraction gas chromatography-mass spectrometry. Heroin appeared rapidly in blood after administration and peaked 1-5 minutes after smoking, which is similar to that observed following intravenous administration. Heroin concentrations declined rapidly to the limit of detection (1.0 ng/mL) by 30 minutes. 6-Acetylmorphine blood concentrations also peaked and declined rapidly after smoked heroin with peak concentrations occurring at 1-2 minutes after smoking. Morphine levels rose and decayed more slowly. Mean elimination half-lives for heroin, 6-acetylmorphine, and morphine were 3.3 min, 5.4 min, and 18.8 min, respectively, by the smoked route. The bioavailability of smoked heroin

78 FR 67048 - Prothioconazole; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-08

... code 111). Animal production (NAICS code 112). Food manufacturing (NAICS code 311). Pesticide manufacturing (NAICS code 32532). B. How can I get electronic access to other related information? You may... Assessment and Determination of Safety Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance...

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

PubMed

Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van't Klooster, Gerben

2015-08-01

Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

Isobolographic Analysis of Pharmacodynamic Interactions between Antifungal Agents and Ciprofloxacin against Candida albicans and Aspergillus fumigatus▿

PubMed Central

Stergiopoulou, Theodouli; Meletiadis, Joseph; Sein, Tin; Papaioannidou, Paraskevi; Tsiouris, Ioannis; Roilides, Emmanuel; Walsh, Thomas J.

2008-01-01

Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Assessment of pharmacodynamic interactions between antifungal and antibacterial agents is complicated by the absence of a common antifungal end point for both agents. Ciprofloxacin has no intrinsic antifungal activity but may interact with antifungal agents, since it inhibits DNA gyrase (topoisomerase II), which is abundant in fungi. We therefore employed isobolographic analysis adapted to incorporate a nonactive agent in order to analyze the potential in vitro interaction between the fluoroquinolone ciprofloxacin and several representative antifungal agents against Candida albicans and Aspergillus fumigatus strains by using a microdilution checkerboard technique. In agreement with earlier in vitro studies, conventional fractional inhibitory concentration index analysis was unable to detect interactions between ciprofloxacin and antifungal agents. However, isobolographic analysis revealed significant pharmacodynamic interactions between antifungal agents and ciprofloxacin against C. albicans and A. fumigatus strains. Amphotericin B demonstrated concentration-dependent interactions for both species, with synergy (interaction indices, 0.14 to 0.81) observed at ciprofloxacin concentrations of <10.64 μg/ml. Synergy (interaction indices, 0.10 to 0.86) was also found for voriconazole and caspofungin against A. fumigatus. Isobolographic analysis may help to elucidate the pharmacodynamic interactions between antifungal and non-antifungal agents and to develop better management strategies against invasive candidiasis and aspergillosis. PMID:18299413

Pharmacodynamically optimized erythropoietin treatment combined with phlebotomy reduction predicted to eliminate blood transfusions in selected preterm infants.

PubMed

Rosebraugh, Matthew R; Widness, John A; Nalbant, Demet; Cress, Gretchen; Veng-Pedersen, Peter

2014-02-01

Preterm very-low-birth-weight (VLBW) infants weighing <1.5 kg at birth develop anemia, often requiring multiple red blood cell transfusions (RBCTx). Because laboratory blood loss is a primary cause of anemia leading to RBCTx in VLBW infants, our purpose was to simulate the extent to which RBCTx can be reduced or eliminated by reducing laboratory blood loss in combination with pharmacodynamically optimized erythropoietin (Epo) treatment. Twenty-six VLBW ventilated infants receiving RBCTx were studied during the first month of life. RBCTx simulations were based on previously published RBCTx criteria and data-driven Epo pharmacodynamic optimization of literature-derived RBC life span and blood volume data corrected for phlebotomy loss. Simulated pharmacodynamic optimization of Epo administration and reduction in phlebotomy by ≥ 55% predicted a complete elimination of RBCTx in 1.0-1.5 kg infants. In infants <1.0 kg with 100% reduction in simulated phlebotomy and optimized Epo administration, a 45% reduction in RBCTx was predicted. The mean blood volume drawn from all infants was 63 ml/kg: 33% required for analysis and 67% discarded. When reduced laboratory blood loss and optimized Epo treatment are combined, marked reductions in RBCTx in ventilated VLBW infants were predicted, particularly among those with birth weights >1.0 kg.

[Safety and tolerability of psychotropic medications in childhood: preliminary data of a pharmacovigilance study].

PubMed

Magazù, A; Masi, G; Germanò, E; Gagliostro, M S; Siracusano, R; Arcoraci, V; Spina, E; Gagliano, A

2014-06-01

The aim of this study was to evaluate adverse drug reactions (ADRs) of psychotropic medications in childhood. One hundred and two children and adolescents (M 82.4%, F 17.6%) followed-up at the Division of Child Neurology and Psychiatry at the University of Messina, and at the Scientific Institute Child Neurology and Psychiatry, IRCCS Stella Maris, Calambrone, Pisa, were recruited between January 2009 and December 2011. All participants met DSM-IV diagnostic criteria for psychiatric disorders. The data were collected using a recording sheet for ADRs. An electronic database was also used. The recording sheet was designed to note all relevant information about drug treatment and ADRs according to AIFA (Agenzia Italiana del Farmaco) suggestions. The most prescribed drugs were: risperidone (19.6%), aripiprazole (18.4%) and valproic acid (14.8%). The ADRs more frequently recorded had been: weight gain (12.6%), sleepiness (8.4%), and irritability (6.7%). None of recorded ADRs were classified as "serious". This study can provide a basic model to collect information on safety and tolerability of psychotropic drugs in childhood.

A controlled, randomized, head-to-head comparison of the Prolieve thermodilatation System versus the Targis System for benign prostatic hyperplasia: safety, procedural tolerability, and clinical results.

PubMed

Shore, Neal D; Sethi, Parminder S

2010-09-01

Compare safety and tolerability of the Prolieve(®) System with the Targis(®) System using objective and subjective measures. Thirty-four men with symptomatic benign prostatic hyperplasia (BPH) were randomized to a single treatment with either the Prolieve or Targis system; 30 were treated and then followed for 6 months. After post-treatment bladder fill with ≥200 mL saline, patients were catheterized if they could not void after 2 hours or had a postvoid residual >150 mL. Catheter use, visual analog scale (VAS) tolerability scores, American Urological Association scores, and safety were assessed. After treatment, 15/16 (94%) Prolieve patients remained catheter-free compared with 3/14 (21%) Targis patients (P = 0.0001). Foley catheter indwelling time was 58.8 hours for the one Prolieve patient compared with 103.9 hrs (range 54-270 h) for the Targis patients (n = 9). Targis patients' catheterization requirements were: Seven Foley only, two intermittent self-catheters only, and two needing both. Intermittent self-catheterization continued for 1 month in two Targis patients. VAS tolerability scores were 24% to 50% lower during Prolieve treatment vs Targis (P < 0.05). Mean AUA scores for Prolieve improved from 21.2 at baseline to 12.3 and 7.9 at week 2 and month 6, respectively; for Targis, AUA scores improved from 22.9 at baseline to 17.9 and 10.9, respectively (P > 0.05). Overall, the incidence of device-related adverse events was 31% (Prolieve) compared with 64% (Targis) (P > 0.05)-most prevalently, urinary retention, dysuria, and hematuria. No device-related serious adverse events occurred. Prolieve provided enhanced near-term therapeutic benefit over Targis as assessed by catheterization, tolerability, and symptom relief, which may assist physician and patient decision-making when selecting an office-based transurethral microwave therapy option for patients.

BIOMARKERS OF OPERATIONAL TOLERANCE IN SOLID ORGAN TRANSPLANTATION

PubMed Central

Heidt, Sebastiaan; Wood, Kathryn J.

2012-01-01

Introduction Long-term immunosuppressive therapy represents a huge burden on transplant recipients, but currently cannot be omitted. Improving long-term transplant outcome by immunosuppressive drug withdrawal may be achieved in patients who have developed (partial) immunological unresponsiveness towards their graft, either spontaneously or through tolerance induction. Reliable biomarkers are essential to define such immunological unresponsiveness and will facilitate controlled immunosuppressive drug weaning as well as provide surrogate end-points for tolerance induction trials. Areas covered Tolerance biomarkers have been defined for both liver and kidney transplantation and can accurately identify operationally tolerant transplant recipients retrospectively. These two tolerance fingerprints are remarkably different, indicating the involvement of distinct mechanisms. Limited data suggest that tolerance biomarkers can be detected in immunosuppressed transplant recipients. Whether these patients can safely have their immunosuppressive drugs withdrawn needs to be established. Expert opinion Mechanistic interpretation of the kidney transplant tolerance biomarker profile dominated by B cell markers remains a challenge in light of experimental evidence suggesting the pivotal involvement of regulatory T cells. Therefore, defining animal models that resemble human transplant tolerance is crucial in understanding the underlying mechanisms. Additionally, to ensure patient safety while monitoring for tolerance, it is essential to develop biomarkers to non-invasively detect early signs of rejection as well. PMID:22988481

Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis

PubMed Central

Lewiecki, E Michael

2011-01-01

Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO) is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture. PMID:22279412

Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus

PubMed Central

Yu, Tian; Enioutina, Elena Y.; Brunner, Hermine I.; Vinks, Alexander A.

2017-01-01

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of childbearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or nonlinear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30–82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60–5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20–79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic

Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus.

PubMed

Yu, Tian; Enioutina, Elena Y; Brunner, Hermine I; Vinks, Alexander A; Sherwin, Catherine M

2017-02-01

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of child-bearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or non-linear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30-82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60-5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20-79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into

Role of Isradipine Loaded Solid Lipid Nanoparticles on the Pharmacodynamic Effect in Rats.

PubMed

Thirupathi, G; Swetha, E; Narendar, D

2017-03-01

Isradipine (ID), is an antihypertensive drug, having low oral bioavailability (15-24%) due to poor aqueous solubility (0.01 mg/mL) and also hepatic first-pass metabolism. Among various approaches, Solid lipid nanoparticles (SLNs) were developed using stearic acid, glyceryl monostearate as lipid matrices for improving the oral bioavailability of ID. ID-SLNs were prepared by using hot homogenization followed by ultrasonication. The prepared SLNs were characterized for size, PDI, zeta potential (ZP), entrapment efficiency (EE) and drug content. In vitro release studies were performed in 0.1NHCl and pH 6.8 phosphate buffer of by open tube method. Physical stability of the SLNs was observed at refrigerated temperature and room temperature for 90 days. Further, pharmacodynamic study was conducted in wistar rats. SLNs prepared with GMS having size of 188.6±3.6 nm, PDI of 0.273±0.052, ZP of - 21.8±2.7 mV with 86.86±0.75% EE were optimized. Differential scanning calorimetric (DSC) study revealed that no interaction between drug and lipid. In vitro release studies showed that more cumulative release of ID in pH 6.8 phosphate buffer than in 0.1NHCl during 24 h. The lyophilized SLN formulation was used in knowing morphology of SLNs, and was found to have spherical shape with increased polydispersity by Scanning electron microscopy. Pharmacodynamic study of SLNs in fructose induced hypertensive rats showed a decrease in systolic blood pressure for 36 h, when compared to suspension, which showed a decrease in systolic blood pressure for only 2 h. Thus, the results conclusively demonstrated the role of SLNs for a significant enhancement in pharmacodynamic effect of ID. © Georg Thieme Verlag KG Stuttgart · New York.

Effect of antibodies to calcitonin on the pharmacokinetics and the pharmacodynamics of the hormone.

PubMed

Tagliaro, F; Dorizzi, R; Luisetto, G

1995-01-01

Calcitonin pharmacokinetics and pharmacodynamics were studied in two groups of patients with postmenopausal osteoporosis, who, treated for one year with intranasal Asu1.7-eel calcitonin (eCT), had (Ab+) and had not (Ab-) developed a specific immune response to the drug. The treatment consisted of daily intranasal administrations of eCT (80 IU/die) with 1 g supplemental calcium. Eight women who had developed specific antibodies and 5 who had not, were given 50 IU of CT i.m., in order to assess the pharmacokinetics and pharmacodynamics of the drug. The rise of serum levels of the hormone was significantly greater in Ab+ than in Ab- patients. At the end of the study, no significant differences in mineral bone loss between the two groups were found. In conclusion, the presence of antibodies to eCT does not represent a negative event in the therapy of osteoporosis, but significantly affects the pharmacokinetics of the drug.

Pharmacokinetic and pharmacodynamic analysis of d-amphetamine in an attention task in rodents.

PubMed

Slezak, Jonathan M; Mueller, Melanie; Ricaurte, George A; Katz, Jonathan L

2018-06-02

Amphetamine is a common therapeutic agent for alleviating the core symptoms associated with attention-deficit hyperactivity disorder (ADHD) in children and adults. The current study used a translational model of attention, the five-choice serial reaction time (5-CSRT) procedure with rats, to examine the time-course effects of d-amphetamine. Effects of different dosages of d-amphetamine were related to drug-plasma concentrations, fashioned after comprehensive pharmacokinetic/pharmacodynamic assessments that have been employed in clinical investigations. We sought to determine whether acute drug-plasma concentrations that enhance performance in the 5-CSRT procedure are similar to those found to be therapeutic in patients diagnosed with ADHD. Results from the pharmacokinetic/pharmacodynamic assessment indicate that d-amphetamine plasma concentrations associated with improved performance on the 5-CSRT procedure overlap with those that have been reported to be therapeutic in clinical trials. The current findings suggest that the 5-CSRT procedure may be a useful preclinical model for predicting the utility of novel ADHD therapeutics and their effective concentrations.

Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses.

PubMed

Lees, Peter; Toutain, Pierre-Louis

2013-06-01

The presence of horse meat in food products destined for human consumption and labelled as beef has raised several concerns of public interest. This review deals solely with one aspect of these concerns; samples of equine tissue from horses destined for the human food chain have tested positive for the non-steroidal anti-inflammatory drug, phenylbutazone. The safety of some or all such foods for human consumers is a major concern, because it was shown many years ago that phenylbutazone therapy in humans can be associated with life threatening blood dyscrasias. As an initial basis for assessing the potential toxicity of foods containing phenylbutazone and its metabolites, this article reviews (1) the pharmacokinetic, pharmacodynamic, metabolic and toxicological profiles of phenylbutazone, with particular reference to horses and humans; (2) toxicity data in laboratory animals; (3) phenylbutazone residues in food producing species, and (4) as a preliminary assessment, the potential hazard associated with the consumption of horse meat containing phenylbutazone and its metabolites. Since phenylbutazone cannot be classified as a carcinogenic substance in humans, and noting that blood dyscrasias in humans are likely to be dose and treatment duration-dependent, the illegal and erratic presence of trace amount residues of phenylbutazone in horse meat is not a public health issue. Copyright © 2013 Elsevier Ltd. All rights reserved.

Salivary Pharmacodynamics and Bioavailability of Promethazine in Human Subjects

NASA Technical Reports Server (NTRS)

Putcha, Lakshmi; Harm, Deborah L.; Nimmagudda, Ram; Berens, Kurt L.; Bourne, David W. A.

1999-01-01

The acute effects of exposure to microgravity include the development of space motion sickness which usually requires therapeutic intervention. The current drug of choice, promethazine (PMZ), has side effects which include nausea, drowsiness, dizziness, sedation and impaired psychomotor performance. In a ground-based study with commercial airline pilots and shuttle simulator trainers, we measured sleep and psychomotor performance variables, and physiological variables such as blood pressure and heart rate, as a function of circulating drug concentrations in the body. We evaluated a non-invasive sampling method (saliva) as a means of assessing pharmacodynamics following a single intramuscular (IM) dose of PMZ.

Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

PubMed Central

Krishna, Rajesh; Stypinski, Daria; Ali, Melissa; Garg, Amit; Cote, Josee; Maes, Andrea; DeGroot, Bruce; Liu, Yang; Li, Susie; Connolly, Sandra M; Wagner, John A; Stoch, S Aubrey

2012-01-01

AIM Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg CoumadinTM) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day −14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC(0–∞) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(−) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin Cmax were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(−) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC(0–168 h) was 0.93 (0.89, 0.96). CONCLUSION The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not

Safety Concerns Surrounding Quinolone Use in Children

PubMed Central

Patel, Karisma; Goldman, Jennifer L.

2016-01-01

Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of distribution, and a broad spectrum of antimicrobial activity. Despite their attractive profile as anti-infective agents, their use in children is limited, primarily due to safety concerns. In this review we highlight the pharmacological properties of fluoroquinolones and describe their current use in pediatrics. In addition, we provide a comprehensive assessment of the safety data associated with fluoroquinolone use in children. Although permanent or destructive arthropathy remains a significant concern, currently available data demonstrate that arthralgia and arthropathy are relatively uncommon in children and resolve following cessation of fluoroquinolone exposure without resulting in long-term sequelae. The concern for safety and risk of adverse events associated with pediatric fluoroquinolone use is likely driving the limited prescribing of this drug class in pediatrics. However, in adults, fluoroquinolones are the most commonly prescribed broad-spectrum antibiotics, resulting in the development of drug-resistant bacteria that can be challenging to treat effectively. The consequence of misuse and overuse of fluoroquinolones leading to drug resistance is a greater, but frequently overlooked, safety concern that applies to both children and adults and one that should be considered at the point of prescribing. PMID:26865283

Time effects of food intake on the pharmacokinetics and pharmacodynamics of quazepam

PubMed Central

Yasui-Furukori, Norio; Takahata, Takenori; Kondo, Tsuyoshi; Mihara, Kazuo; Kaneko, Sunao; Tateishi, Tomonori

2003-01-01

Aims There is little information on interaction between food and the hypnotic agent quazepam. We therefore studied the effects of food and its time interval on the pharmacokinetics and pharmacodynamics of quazepam. Methods A randomized three-phase crossover study with 2-week intervals was conducted. Nine healthy male volunteers took a single oral 20 mg dose of quazepam under the following conditions: 1) after fasting overnight; 2) 30 min after eating standard meal; or 3) 3 h after eating the same meal. Plasma concentrations of quazepam and its metabolite, 2-oxoquazepam and psychomotor function using the Digit Symbol Substitute Test (DSST), Stanford Sleepiness Scale (SSS) and Visual Analogue Scale were measured up to 48 h. Results During the food treatments at 30 min and 3 h before dosing, the peak concentrations (Cmax) were 300% (95% CI 260, 340%; P < 0.001) and 250% (95% CI 210, 290%; P < 0.01) of the corresponding value during the fasting phase. For quazepam, the area under the plasma concentration–time curve from 0 to 8 h measured at 30 min and 3 h before dosing was significantly increased, with the food treatments by 2.4-fold (95% CI 2.0; 2.8-fold; P < 0.001) and 2.1-fold (95% CI 1.7; 2.4-fold; P < 0.01), respectively. In response to pharmacokinetic changes, some of the pharmacodynamics (DSST, P < 0.05; SSS, P < 0.05) differed significantly between fasted status and fed status. No difference was found in any pharmacokinetic or pharmacodynamic parameters between the two food treatment phases. Conclusions A food effect on quazepam absorption is evident and continues at least until 3 h after food intake. The dosing of quazepam after a long period of ordinary fasting might reduce its efficacy because a 3 h interval between the timing of the evening meal and bedtime administration of hypnotics is regarded as normal in daily life. PMID:12680887

Bioavailability and Pharmacodynamics of Promethazine on Long Duration Missions to the International Space Station

NASA Technical Reports Server (NTRS)

Putcha, Lakshmi; Boyd, Jason L.; Cintron, Nitza; Berens, Kurt L.

2004-01-01

Space motion sickness (SMS) is often treated in space with promethazine (PMZ). Common side effects of PMZ administration (50 mg intramuscular) on the ground are drowsiness and impaired cognitive performance. Anecdotal reports indicate that these effects are absent or less pronounced in space. This suggests that the availability of PMZ to the body (bioavailability) and/or the response of the body to PMZ (pharmacodynamics) may change during space flight. Opportunities for clinical research in space are limited. The study described here is our response to a NASA Research Announcement for proposals for flight-based research needed to improve, or answer specific questions about, diagnosis and therapy during space flight, and post-flight rehabilitation. We propose here to evaluate noninvasive methods for determining the bioavailability and pharmacodynamics of PMZ. The specific objectives of the proposed research are to 1) compare pharmacokinetic and pharmacodynamic parameters of PMZ, estimated from saliva and plasma levels after administration of PMZ, 2) estimate the relative bioavailability of the three dosage forms of PMZ that are often administered to control motion sickness symptoms in space, and 3) establish the dose-response relationship of PMZ. We will estimate the bioavailability of an intramuscular injection (IM), oral tablet, and rectal suppository of PMZ in noma1 subjects during ambulatory and antiorthostatic bed rest (ABR) conditions using novel stable isotope techniques. We will compare and contrast the bioavailability of PMZ during normal and microgravity conditions to examine changes in drug absorption and bioavailability during microgravit. Results of this study will validate methods for an approved in-flight investigation with this medication awaiting an opportunity for manifestation..

Pharmacodynamic comparison of two formulations of Acarbose 100-mg tablets.

PubMed

Lee, S; Chung, J Y; Hong, K S; Yang, S-H; Byun, S-Y; Lim, H-S; Shin, S-G; Jang, I-J; Yu, K-S

2012-10-01

Acarbose, an α-glycosidase inhibitor, is used to treat diabetic patients. Pharmacokinetic evaluation of acarbose is difficult because <2% is absorbed systemically. The current investigation evaluated the bioequivalence of two formulations of acarbose through pharmacodynamic comparison. This investigation consisted of a pilot study and a main study. The pilot study had an open, single-dose, single-sequence design. Subjects received placebo and then two tablets of reference formulation (Glucobay(®) 100 mg tablet; Bayer Healthcare) on two consecutive days with sucrose. The main study was an open, randomized, two-period, two-sequence crossover study. Subjects randomly received placebo and two tablets of either test formulation (generic acarbose 100-mg tablet) or reference formulation with sucrose on two consecutive days in the first period. In the second period, placebo and alternative formulation were administered. Serial blood samples for pharmacodynamic assessment were taken after each administration. The maximum serum glucose concentration (G(max)) and the area under the serum glucose concentration-time profile (AUC(gluc)) were determined and compared. Five subjects completed the pilot study. The AUC(gluc) from dosing until 1 h post-dose (AUC(gluc,1 h)) was significantly different between the placebo and acarbose. A total of 33 subjects completed the main study. The mean differences in G(max) (ΔG(max)) and AUC(gluc,1 h) (ΔAUC(gluc,1 h)) for the reference formulation compared with placebo were 22·0 ± 18·3 mg/dL and 928·2 ± 756·0 mg min/dL, respectively. The corresponding values for the test formulation were 23·3 ± 21·2 mg/dL and 923·0 ± 991·4 0 mg min/dL, respectively. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for ΔG(max) and ΔAUC(gluc, 1 h) were 1·06 and 1·00, respectively, and the 90% confidence intervals (CIs) corresponding values were 0·79-1·39 and 0·64-1·36, respectively. The 90% CIs of GMRs

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

PubMed Central

Mahr, Benedikt; Granofszky, Nicolas; Muckenhuber, Moritz; Wekerle, Thomas

2017-01-01

The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing graft-vs.-host disease (GVHD) constitute the most prohibitive hurdles. However, several approaches have recently been developed at the experimental level to reduce or even overcome the necessity for cytoreductive conditioning, such as costimulation blockade, pro-apoptotic drugs, or Treg therapy. But even in the absence of any hazardous pretreatment, the recipients are exposed to the risk of developing GVHD as long as non-tolerant donor T cells are present. Total lymphoid irradiation and enriching the stem cell graft with facilitating cells emerged as potential strategies to reduce this peril. On the other hand, the long-lasting survival of kidney allografts, seen with transient chimerism in some clinical series, questions the need for durable chimerism for robust tolerance. From a safety point of view, loss of chimerism would indeed be favorable as it eliminates the risk of GVHD, but also complicates the assessment of tolerance. Therefore, other biomarkers are warranted to monitor tolerance and to identify those patients who can safely be weaned off immunosuppression. In addition to these safety concerns, the limited efficacy of the current pilot trials with approximately 40–60% patients becoming tolerant remains an important issue that needs to be resolved. Overall, the road ahead to clinical routine may still be rocky but the first successful long-term patients and progress

Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

PubMed

Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

2009-05-01

This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

PubMed Central

Urbano, Paulo César Martins; Soccol, Vanete Thomaz; Azevedo, Valderilio Feijó

2014-01-01

Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α) raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products). This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation. PMID:25114503

Nanostructured lipid carriers-based flurbiprofen gel after topical administration: acute skin irritation, pharmacodynamics, and percutaneous absorption mechanism.

PubMed

Song, Aihua; Su, Zhen; Li, Sanming; Han, Fei

2015-01-01

In order to assess the preliminary safety and effectiveness of nanostructured lipid carriers-based flurbiprofen gel (FP NLC-gel), the acute irritation test, in vivo pharmacodynamics evaluation and pharmacokinetic study were investigated after topical application. No dropsy and erythema were observed after continuous dosing 7 d of FP NLC-gel on the rabbit skin, and the xylene-induced ear drossy could be inhibited by FP NLC-gel at different dosages. The maximum concentration of FP in rats muscle was 2.03 μg/g and 1.55 μg/g after oral and topical administration, respectively. While the peak concentration in untreated muscle after topical administration was only 0.37 μg/mL. And at any time, following topical administration the mean muscle-plasma concentration ratio Cmuscle/CPlasma was obviously higher than that following oral administration. Results indicated that FP could directly penetrate into the subcutaneous muscle tissue from the administration site. Thus, the developed FP NLC-gel could be a safe and effective vehicle for topical delivery of FP.

SAFETY AND TOLERABILITY OF LOW DOSE NALTREXONE THERAPY IN CHILDREN WITH MODERATE TO SEVERE CROHN’S DISEASE: A PILOT STUDY

PubMed Central

Smith, Jill P.; Field, Douglas; Bingaman, Sandra; Evans, Robert; Mauger, David

2012-01-01

Background There is an unmet need for safe and effective medicines to treat children with Crohn’s disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells. Aims The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn’s disease. Methods A pilot clinical trial was conducted in children with moderate to severe Crohn’s disease. Fourteen subjects with a mean age of 12.3 years (8–17, range) were enrolled. Children were randomized to placebo or naltrexone 0.1 mg/kg orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the PCDAI (Pediatric Crohn’s Disease Activity Index) and Quality of life was monitored by the Impact III survey. Results Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn’s disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an eight-week course of naltrexone therapy (21.7±3.9) (p=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score < 10) and 67% had improved with mild disease activity (decrease PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (p=0.035). Conclusions Naltrexone therapy appears safe with limited toxicity when given to children with Crohn’s disease and may reduce disease activity. PMID:23188075

A Historical View and Vision into the Future of the Field of Safety Pharmacology.

PubMed

Bass, Alan S; Hombo, Toshiyasu; Kasai, Chieko; Kinter, Lewis B; Valentin, Jean-Pierre

2015-01-01

Professor Gerhard Zbinden recognized in the 1970s that the standards of the day for testing new candidate drugs in preclinical toxicity studies failed to identify acute pharmacodynamic adverse events that had the potential to harm participants in clinical trials. From his vision emerged the field of safety pharmacology, formally defined in the International Conference on Harmonization (ICH) S7A guidelines as "those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above." Initially, evaluations of small-molecule pharmacodynamic safety utilized efficacy models and were an ancillary responsibility of discovery scientists. However, over time, the relationship of these studies to overall safety was reflected by the regulatory agencies who, in directing the practice of safety pharmacology through guidance documents, prompted transition of responsibility to drug safety departments (e.g., toxicology). Events that have further shaped the field over the past 15 years include the ICH S7B guidance, evolution of molecular technologies leading to identification of new therapeutic targets with uncertain toxicities, introduction of data collection using more sophisticated and refined technologies, and utilization of transgenic animal models probing critical scientific questions regarding novel targets of toxicity. The collapse of the worldwide economy in the latter half of the first decade of the twenty-first century, continuing high rates of compound attrition during clinical development and post-approval and sharply increasing costs of drug development have led to significant strategy changes, contraction of the size of pharmaceutical organizations, and refocusing of therapeutic areas of investigation. With these changes has come movement away from dedicated internal safety pharmacology capability to utilization of capabilities within external contract

Phase I study evaluating the safety, tolerability and pharmacokinetics of a novel oral dissolvable film containing dexamethasone versus Fortecortin dexamethasone tablets.

PubMed

Diamant, Zuzana; Samuelsson Palmgren, Gabriella; Westrin, Bengt; Bjermer, Leif

2017-01-01

Introduction : Systemic corticosteroids are anti-inflammatory agents with dexamethasone among the most potent in the class. Within (respiratory) allergy, systemic corticosteroids are usually applied in medical emergencies. In these situations, patients may experience physical or logistic problems taking tablets. To fulfil a practical unmet need for outpatients, Dexa ODF, an oral dissolvable film containing dexamethasone, was developed. Objectives : We compared the safety, tolerability and pharmacokinetics (PK) of Dexa ODF with Fortecortin tablets in healthy subjects. Methods : Thirty subjects participated in this open label, two-way, cross-over study, consisting of two treatment visits separated by 5-10 days. On both treatment visits, subjects randomly received one single dose of Dexa ODF (one strip; 8 mg dexamethasone) or one single dose of Fortecortin (two 4 mg tablets). Safety evaluations and blood sampling for PK were conducted until 48 h post-dose and bioequivalence analysis was performed on AUC(0-t), AUC(0-∞) and Cmax. Results : All subjects were dosed. Forty-five adverse events (AEs) were reported by 17 subjects and approximately 50% were deemed 'possibly treatment related' (14 on Dexa ODF; 12 on Fortecortin) with no significant difference between treatments. For all three bioequivalence parameters the 90% CIs were within the acceptance limits of bioequivalence (0.8;1.25). Conclusion : We demonstrated good tolerability and bioequivalence of Dexa ODF (8 mg dexamethasone) compared to Fortecortin tablets (2 × 4 mg dexamethasone). Dexa ODF is currently under development as an innovative treatment for use within respiratory and allergic conditions, including emergencies.

Efficacy, tolerability, and safety of aripiprazole once-monthly versus other long-acting injectable antipsychotic therapies in the maintenance treatment of schizophrenia: a mixed treatment comparison of double-blind randomized clinical trials.

PubMed

Majer, Istvan M; Gaughran, Fiona; Sapin, Christophe; Beillat, Maud; Treur, Maarten

2015-01-01

Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia. This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety. A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013. Studies were required to have ≥24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo. Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms. Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant

Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

PubMed Central

Lee, S-H; Ghim, J-L; Song, M-H; Choi, H-G; Choi, B-M; Lee, H-M; Lee, E-K; Roh, Y-J; Noh, G-J

2009-01-01

Background and purpose: Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations. Experimental approach: The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg−1·min−1) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling. Key results: Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUClast and AUCinf between both formulations were acceptable for bioequivalence, whereas that of Cmax was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E0 (baseline ApEn)–Emax (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V1 of both formulations and sex for k21 of microemulsion propofol. The blood-brain equilibration rate constants (ke0, min−1) were 0.476 and 0.696 for microemulsion and LCT propofol respectively. Conclusions and implications: Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges. PMID:19925493

Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.

PubMed

Herbst, Roy S; Hong, David; Chap, Linnea; Kurzrock, Razelle; Jackson, Edward; Silverman, Jeffrey M; Rasmussen, Erik; Sun, Yu-Nien; Zhong, Don; Hwang, Yuying C; Evelhoch, Jeffrey L; Oliner, Jonathan D; Le, Ngocdiep; Rosen, Lee S

2009-07-20

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient

Pharmacokinetic and Pharmacodynamic Interaction of Andrographolide and Standardized Extract of Andrographis paniculata (Nees) with Nabumetone in Wistar Rats.

PubMed

Balap, Aishwarya; Lohidasan, Sathiyanarayanan; Sinnathambi, Arulmozhi; Mahadik, Kakasaheb

2017-01-01

The aim of the study was to investigate the herb-drug interaction of Andrographis paniculata Nees (Acanthaceae) and Andrographolide (AN) with nabumetone (NAB) in wistar rats. Pharmacokinetic and pharmacodynamic interactions were studied after co-administration of APE and AN with NAB in Wistar rats. In pharmacokinetic studies, significant decrease in Cmax, AUC 0-t and AUC 0-∞ of 6-MNA after co-administration with pure AN and APE has been observed. T max of 6-MNA has been increased to 2 h from 1.5 h in AN + NAB treated group. Changes in mean residential time, clearance and volume of distribution of 6-MNA in APE + NAB treated group and AN + NAB treated group indicated interference of other components of APE other than AN. In pharmacodynamic study, significant decrease in antiarthritic activity of NAB on concomitant administration with APE and AN has been observed. The study concludes that NAB exhibits pharmacokinetic and pharmacodynamic interactions with APE and AN in rats thus alarms the concomitant use of herbal preparations containing APE and AN with NAB. Further study is needed to understand the mechanism and predict the herb-drug interaction in humans. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Curcumin-Zn(II) complex for enhanced solubility and stability: an approach for improved delivery and pharmacodynamic effects.

PubMed

Sareen, Rashmi; Jain, Nitin; Dhar, K L

2016-08-01

The aim of present investigation was to prepare Curcumin-Zn(II) complex in a view to enhance solubility, stability and pharmacodynamic effect in experimentally induced ulcerative colitis. Curcumin-Zn(II) complex was prepared by stirring curcumin with anhydrous zinc chloride at a molar ratio of 1:1. The prepared curcumin metallocomplex was characterized by TLC, FTIR, UV spectroscopy and (1)H NMR. In vitro kinetic degradation and solubility of Curcumin and Curcumin-Zn(II) complex was analyzed spectrophotometrically. Pharmacodynamic evaluation of curcumin and its metal complex was assessed in ulcerative colitis in mice. Curcumin showed chelation with zinc ion as confirmed by the TLC, FTIR, UV spectroscopy and (1)H NMR. The results of TLC [Rf value], IR Spectroscopy [shifting of stretching vibrations of υ(C=C) and υ(C=O)], UV spectra [deconvoluted with absorption band at 432-466.4 nm] of Curcumin-Zn(II) complex compared to curcumin confirmed the formation of metallocomplex. (1)HNMR spectra of Curcumin-Zn(II) showed the upfield shift of Ha and Hb. Kinetic stability studies showed metallocomplex with zinc exhibited good stability. In vivo study revealed significant reduction in severity and extent of colonic damage with Curcumin-Zn(II) which were further confirmed by histopathological study. This study recognizes higher solubility and stability of Curcumin-Zn(II) complex and suggested better pharmacodynamic effects.

Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.

PubMed

Odenholt, Inga; Walder, Mats; Wullt, Marlene

2007-01-01

Pharmacodynamic studies of antibiotics have attracted great interest in recent years. However, studies on the pharmacodynamics of different antibiotics against Clostridium difficile are scarce. The postantibiotic effects (PAE) and the postantibiotic sub-minimum inhibitory concentration (MIC) effects (PA SME) of vancomycin, metronidazole and fusidic acid were investigated by viable counts against three different strains of C. difficile. The killing rate and extent of the three antibiotics against the same strains were also studied by adding 2, 4, 8, 16 and 32x MIC of the three antibiotics, respectively. Metronidazole exerted a very rapid bactericidal effect at concentrations of 8x MIC and above against all three strains investigated. Vancomycin gave overall less kill in comparison to metronidazole and was bacteriostatic against two of the three strains. Fusidic acid exerted a concentration-dependent killing against two of the strains. Vancomycin exerted short PAEs and PA SMEs against all three strains. Significantly longer PAEs and PA SMEs were noted for fusidic acid. Metronidazole gave similar short PAEs like vancomycin but longer PA SMEs were noted against two of the investigated strains. Metronidazole exerted the most prominent bactericidal effect greater than fusidic acid and greater than vancomycin. Fusidic acid gave overall the longest PAEs and PA SMEs greater than metronidazole and greater than vancomycin. Copyright 2007 S. Karger AG, Basel.

Pharmacokinetics and Pharmacodynamics of Luseogliflozin, a Selective SGLT2 Inhibitor, in Japanese Patients With Type 2 Diabetes With Mild to Severe Renal Impairment.

PubMed

Samukawa, Yoshishige; Haneda, Masakazu; Seino, Yutaka; Sasaki, Takashi; Fukatsu, Atsushi; Kubo, Yusuke; Sato, Yuri; Sakai, Soichi

2018-04-25

This open-label, parallel-group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5-mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; ≥90, 60-89, 45-59, 30-44, 15-29 mL/min/1.73 m 2 , respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment. © 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Lack of clinical pharmacodynamic and pharmacokinetic drug-drug interactions between warfarin and the antisense oligonucleotide mipomersen.

PubMed

Li, Zhaoyang; Hard, Marjie L; Grundy, John S; Singh, Tejdip; von Moltke, Lisa L; Boltje, Ingrid

2014-08-01

Mipomersen is a second-generation antisense oligonucleotide indicated as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH). Warfarin is commonly prescribed for a variety of cardiac disorders in homozygous familial hypercholesterolemia population, and concurrent use of warfarin and mipomersen is likely. This open-label, single-sequence 2-period phase 1 study in healthy subjects evaluated the potential drug-drug interactions between mipomersen and warfarin. The subjects received a single oral 25 mg dose of warfarin alone on day 1, and after a 7-day washout period, received 200 mg mipomersen alone subcutaneously every other day on days 8-12, and received both concurrently on day 14. Coadministration of mipomersen did not change the pharmacodynamics (international normalized ratio, prothrombin time, and activated partial thromboplastin time) and pharmacokinetics (PK) of warfarin. There were no clinically significant changes in the PK of mipomersen with concurrent administration of warfarin. There were no events indicative of an increase in bleeding tendency when warfarin was coadministered with mipomersen, and the adverse event profile of mipomersen did not appear to be altered in combination with warfarin, as compared with that of the respective reference treatment. The combination of these 2 medications appeared to be safe and well tolerated. These results suggest that the dosage adjustment of warfarin or mipomersen is not expected to be necessary with coadministration.

A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data.

PubMed

Jonker, Daniël M; Kenna, Leslie A; Leishman, Derek; Wallis, Rob; Milligan, Peter A; Jonsson, E Niclas

2005-06-01

QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT prolongation in humans for the class III antiarrhythmic dofetilide. The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease). A population pharmacokinetic-pharmacodynamic analysis of the in vitro and in vivo data was performed in NONMEM by use of the operational model of pharmacologic agonism to estimate the efficiency of transduction from ion channel binding to Fridericia-corrected QT response. A 3-compartment pharmacokinetic model with first-order absorption characterized the time course of dofetilide concentrations. On the basis of an in vitro potency of 5.13 ng/mL for potassium current inhibition and predicted unbound dofetilide concentrations, the estimated transducer ratio (tau) of 6.2 suggests that the QT response plateaus before currents are fully blocked. In our study population, 10% hERG blockade corresponds to a QT prolongation of 20 ms (95% confidence interval, 12-32 ms). With long-term dofetilide administration, tolerance develops with a half-life of 4.7 days. The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties.

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies

PubMed Central

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-01-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5–20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5–20mg/day) was 4.5–7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5–20mg/day) were nausea (20.9–31.2%) and vomiting (2.9–6.5%). For vortioxetine (5–20mg/day), the incidence of TEAEs associated with insomnia was 2.0–5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6–1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7–0.8kg. Thus, vortioxetine (5–20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. PMID:26864543

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies.

PubMed

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-03-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5-20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5-20mg/day) was 4.5-7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5-20mg/day) were nausea (20.9-31.2%) and vomiting (2.9-6.5%). For vortioxetine (5-20mg/day), the incidence of TEAEs associated with insomnia was 2.0-5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6-1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7-0.8kg. Thus, vortioxetine (5-20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. © The Author(s) 2016.

Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.

PubMed

Ault, Alida; Tennant, Sharon M; Gorres, J Patrick; Eckhaus, Michael; Sandler, Netanya G; Roque, Annelys; Livio, Sofie; Bao, Saran; Foulds, Kathryn E; Kao, Shing-Fen; Roederer, Mario; Schmidlein, Patrick; Boyd, Mary Adetinuke; Pasetti, Marcela F; Douek, Daniel C; Estes, Jacob D; Nabel, Gary J; Levine, Myron M; Rao, Srinivas S

2013-12-02

Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques. Copyright © 2013. Published by Elsevier Ltd.

Propulsion Health Monitoring for Enhanced Safety

NASA Technical Reports Server (NTRS)

Butz, Mark G.; Rodriguez, Hector M.

2003-01-01

This report presents the results of the NASA contract Propulsion System Health Management for Enhanced Safety performed by General Electric Aircraft Engines (GE AE), General Electric Global Research (GE GR), and Pennsylvania State University Applied Research Laboratory (PSU ARL) under the NASA Aviation Safety Program. This activity supports the overall goal of enhanced civil aviation safety through a reduction in the occurrence of safety-significant propulsion system malfunctions. Specific objectives are to develop and demonstrate vibration diagnostics techniques for the on-line detection of turbine rotor disk cracks, and model-based fault tolerant control techniques for the prevention and mitigation of in-flight engine shutdown, surge/stall, and flameout events. The disk crack detection work was performed by GE GR which focused on a radial-mode vibration monitoring technique, and PSU ARL which focused on a torsional-mode vibration monitoring technique. GE AE performed the Model-Based Fault Tolerant Control work which focused on the development of analytical techniques for detecting, isolating, and accommodating gas-path faults.

Pharmacodynamic study on insomnia-curing effects of Shuangxia Decoction in Drosophila melanogaster.

PubMed

Zhang, Zhi-Qian; Degejin; Geng, Di; Zhang, Qi; Tian, Yan; Xi, Yuan; Wang, Wen-Qi; Tang, Hua-Qi; Xu, Bing; Lin, Hong-Ying; Sun, Yi-Kun

2016-09-01

The present study aimed to establish a pharmacodynamic method using the pySolo software to explore the influence of freeze-dried powders of Shuangxia Decoction (SXD) on the sleep of normal Drosophila melanogaster and the Drosophila melanogaster whose sleep was divested by light. The dose-effect and the time-effect relationships of SXD on sleep were examined. The effect-onset concentration of SXD was 0.25%, the plateau appeared at the concentration of 2.5% and the total sleep time showed a downtrend when the concentration was greater than 2.5%. The sleep time was the longest on the fourth day after SXD was given. The fruit fly sleep deprivation model was repeated by light stimulation at night. The middle dosage group (2.5%) had the best insomnia-curing effect. In conclusion, using the pySolo software, an approach for the pharmacodynamics study was established with Drosophila melanogaster as a model organism to determine the insomnia-curing effects of the traditional Chinese medicine (TCM). Our results demonstrated the reliability of this method. The freeze-dried powders of SXD could effectively improve the sleep quality of Drosophila melanogaster. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers.

PubMed

McLeod, J F; Leempoels, J M; Peng, S X; Dax, S L; Myers, L J; Golder, F J

2014-11-01

Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers. Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h. Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h). GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies].

PubMed

Petzke, F; Enax-Krumova, E K; Häuser, W

2016-02-01

Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2  with nabilone and 1  with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

PubMed Central

Adjei, Alex A.; Cohen, Roger B.; Franklin, Wilbur; Morris, Clive; Wilson, David; Molina, Julian R.; Hanson, Lorelei J.; Gore, Lia; Chow, Laura; Leong, Stephen; Maloney, Lara; Gordon, Gilad; Simmons, Heidi; Marlow, Allison; Litwiler, Kevin; Brown, Suzy; Poch, Gregory; Kane, Katie; Haney, Jerry; Eckhardt, S. Gail

2009-01-01

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. PMID:18390968

Population Pharmacokinetic/Pharmacodynamic Analysis of Alirocumab in Healthy Volunteers or Hypercholesterolemic Subjects Using an Indirect Response Model to Predict Low-Density Lipoprotein Cholesterol Lowering: Support for a Biologics License Application Submission: Part II.

PubMed

Nicolas, Xavier; Djebli, Nassim; Rauch, Clémence; Brunet, Aurélie; Hurbin, Fabrice; Martinez, Jean-Marie; Fabre, David

2018-05-03

Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. From a dataset of 2799 individuals (14,346 low-density lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing low-density lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual low-density lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in low-density lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain between-subject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. This model successfully allowed the

How do the top 12 pharmaceutical companies operate safety pharmacology?

PubMed

Ewart, Lorna; Gallacher, David J; Gintant, Gary; Guillon, Jean-Michel; Leishman, Derek; Levesque, Paul; McMahon, Nick; Mylecraine, Lou; Sanders, Martin; Suter, Willi; Wallis, Rob; Valentin, Jean-Pierre

2012-09-01

How does safety pharmacology operate in large pharmaceutical companies today? By understanding our current position, can we prepare safety pharmacology to successfully navigate the complex process of drug discovery and development? A short anonymous survey was conducted, by invitation, to safety pharmacology representatives of the top 12 pharmaceutical companies, as defined by 2009 revenue figures. A series of multiple choice questions was designed to explore group size, accountabilities, roles and responsibilities of group members, outsourcing policy and publication record. A 92% response rate was obtained. Six out of 11 companies have 10 to 30 full time equivalents in safety pharmacology, who hold similar roles and responsibilities; although the majority of members are not qualified at PhD level or equivalent. Accountabilities were similar across companies and all groups have accountability for core battery in vivo studies and problem solving activities but differences do exist for example with in vitro safety screening and pharmacodynamic/pharmokinetic modeling (PK/PD). The majority of companies outsource less than 25% of studies, with in vitro profiling being the most commonly outsourced activity. Finally, safety pharmacology groups are publishing 1 to 4 articles each year. This short survey has highlighted areas of similarity and differences in the way large pharmaceutical companies operate safety pharmacology. Copyright © 2012 Elsevier Inc. All rights reserved.

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma

PubMed Central

Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno

2017-01-01

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans’ solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas. PMID:28505195

Detectable Tenofovir Levels in Breast-Feeding Infants of Mothers Exposed to Topical Tenofovir.

PubMed

Noguchi, Lisa M; Montgomery, Elizabeth T; Biggio, Joseph R; Hendrix, Craig W; Bogen, Debra L; Hillier, Sharon L; Dai, James Y; Piper, Jeanna M; Marzinke, Mark A; Dezzutti, Charlene S; Isaacs, S Karen; Schwartz, Jill L; Watts, D Heather; Beigi, Richard H

2016-09-01

Lactation studies are necessary evaluations of medications for reproductive-age women. We evaluated pharmacokinetics (PK), pharmacodynamics, safety, and adherence profiles associated with 7 days of 1% tenofovir (TFV) vaginal gel use during lactation. Tenofovir levels (maternal/infant serum, milk) and anti-HIV activity (milk), adverse events (AEs), and adherence were measured for 17 HIV-1-seronegative breast-feeding mother-infant pairs. Tenofovir use was well-tolerated and detected at low levels in maternal serum, milk, and infant serum but demonstrated no anti-HIV activity in milk. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Safety and tolerability profile of daclizumab in patients with relapsing-remitting multiple sclerosis: An integrated analysis of clinical studies.

PubMed

Giovannoni, Gavin; Kappos, Ludwig; Gold, Ralf; Khatri, Bhupendra O; Selmaj, Krzysztof; Umans, Kimberly; Greenberg, Steven J; Sweetser, Marianne; Elkins, Jacob; McCroskery, Peter

2016-09-01

Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication. Evaluate the safety of daclizumab in patients with RRMS from an integrated analysis of six clinical studies. Patients treated with at least one dose of subcutaneous daclizumab 150mg or 300mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint. This analysis included 2236 patients with 5214 patient-years of exposure to daclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment. This integrated analysis demonstrates that treatment of RRMS with daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells

PubMed Central

Chudasama, Vaishali L.; Ovacik, Meric A.; Abernethy, Darrell R.

2015-01-01

Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of intersubject variability and adverse drug reactions. However, most models of biological systems are qualitative and are not easily coupled with dynamical models of drug exposure-response relationships. In this proof-of-concept study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells is used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes. Bortezomib is a commonly used first-line agent in MM treatment; however, knowledge of the signal transduction pathways regulating bortezomib-mediated cell cytotoxicity is incomplete. A Boolean network model of 66 nodes was constructed that includes major survival and apoptotic pathways and was updated using responses to several chemical probes. Simulated responses to bortezomib were in good agreement with experimental data, and a reduction algorithm was used to identify key signaling proteins. Bortezomib-mediated apoptosis was not associated with suppression of nuclear factor κB (NFκB) protein inhibition in this cell line, which contradicts a major hypothesis of bortezomib pharmacodynamics. A pharmacodynamic model was developed that included three critical proteins (phospho-NFκB, BclxL, and cleaved poly (ADP ribose) polymerase). Model-fitted protein dynamics and cell proliferation profiles agreed with experimental data, and the model-predicted IC50 (3.5 nM) is comparable to the experimental value (1.5 nM). The cell-based pharmacodynamic model successfully links bortezomib exposure to MM cellular proliferation via protein dynamics, and this model may show utility in exploring bortezomib-based combination regimens. PMID:26163548

The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease

PubMed Central

Edwards, Nicola C; Steeds, Richard P; Chue, Colin D; Stewart, Paul M; Ferro, Charles J; Townend, Jonathan N

2012-01-01

AIM Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30–89 ml/min/1.73m2) received 25 mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. RESULTS After 40 weeks of treatment the incidence of serious hyperkalaemia (K+≥6.0 mmol/L) was <1%. A potassium 5.5–5.9 mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0 mmol/L and eGFR ≤45 ml/min/1.73m2. Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. CONCLUSION Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested. PMID:21950312

The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease.

PubMed

Edwards, Nicola C; Steeds, Richard P; Chue, Colin D; Stewart, Paul M; Ferro, Charles J; Townend, Jonathan N

2012-03-01

Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30-89ml/min/1.73m(2) ) received 25mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. After 40 weeks of treatment the incidence of serious hyperkalaemia (K(+) ≥6.0mmol/L) was <1%. A potassium 5.5-5.9mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0mmol/L and eGFR ≤45 ml/min/1.73m(2) . Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, SUVN-502, in Healthy Young Adults and Elderly Subjects.

PubMed

Nirogi, Ramakrishna; Mudigonda, Koteshwara; Bhyrapuneni, Gopinadh; Muddana, Nageswara Rao; Goyal, Vinod Kumar; Pandey, Santosh Kumar; Palacharla, Raghava Choudary

2018-05-01

SUVN-502, a selective 5-HT6 receptor antagonist, was found to be active in preclinical models of cognitive deterioration suggesting a potential role in the treatment of dementia related to Alzheimer's disease. The objective of this study was to characterize the safety, tolerability and pharmacokinetics of SUVN-502 in healthy young adults and elderly subjects following single and multiple oral doses. Single doses (5, 15, 50, 100 and 200 mg SUVN-502) and multiple doses (50, 100 and 130 mg SUVN-502 once daily for 7 days) were evaluated in healthy young adults and multiple doses (50 and 100 mg SUVN-502 once daily for 14 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food, gender and age on SUVN-502 pharmacokinetics (100 mg single dose) was evaluated using an open-label, two-period, randomized, fed and fasted in a crossover design. SUVN-502 and M1 (major metabolite of SUVN-502) were monitored using validated analytical methods. SUVN-502 is safe and well tolerated up to the highest tested single dose of 200 mg in healthy young adults and multiple doses up to 130 mg for 7 days and 100 mg for 14 days in healthy young adults and elderly subjects, respectively. Exposures of SUVN-502 and M1 were more than dose-proportional over the evaluated dose range. Food and gender did not have a clinically meaningful effect on SUVN-502 exposure. The mean SUVN-502 total (AUC 0-∞ , and AUC 0-last ) and peak exposures (C max ) were 2.9- and 2.2-fold higher, respectively, in elderly subjects compared to young subjects. Steady-state was achieved for SUVN-502 and M1 within 7 days after once-daily dosing of SUVN-502. SUVN-502 exhibited an acceptable safety, tolerability and pharmacokinetic profile in healthy young adults and elderly subjects. Based on the above results, 50 and 100 mg once-daily doses of SUVN-502 were advanced to Phase 2 evaluation in patients with moderate AD.

Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children.

PubMed

Esposito, Susanna; Giavoli, Claudia; Trombetta, Claudia; Bianchini, Sonia; Montinaro, Valentina; Spada, Anna; Montomoli, Emanuele; Principi, Nicola

2016-01-02

Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3-14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p<0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p<0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p<0.01 for GMT values and p<0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Pharmacokinetic/Pharmacodynamic Model of Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia Patients Treated with Flavopiridol

PubMed Central

Ji, Jia; Mould, Diane R.; Blum, Kristie A.; Ruppert, Amy S.; Poi, Ming; Zhao, Yuan; Johnson, Amy J.; Byrd, John C.; Grever, Michael R.; Phelps, Mitch A.

2013-01-01

Purpose Flavopiridol, the first clinically evaluated cyclin dependent kinase inhibitor, demonstrates activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS. Experimental Design A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates. Results Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy < 10 cm or > 10 cm during the first two treatments was 0.111 (SE% 13.0%) and 0.265, (SE% 17.9%) respectively, when flavo-G area under the plasma concentration vs. time curve was at its median value in whole patient group. Conclusions This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine if the associations between TLS, gender and glucuronide metabolites are relevant in CLL patients treated with other cyclin dependent kinase inhibitors. PMID:23300276

Effects of Gymnema sylvestre extract on the pharmacokinetics and pharmacodynamics of glimepiride in streptozotocin induced diabetic rats.

PubMed

Kamble, Bhagyashree; Gupta, Ankur; Moothedath, Ismail; Khatal, Laxman; Janrao, Shirish; Jadhav, Amol; Duraiswamy, B

2016-02-05

Gymnema sylvestre, important Indian traditional herbal medicine has been used for diabetes from several years and marketed as single or multi-herb formulations globally. People are consuming G. sylvestre along with conventional hypoglycemic drugs. Therefore, there is need of evidence based assessment of risk versus benefits when G. sylvestre co-administered with conventional oral hypoglycemic drugs. In present investigation, pharmacodynamics and pharmacokinetic interactions with oral hypoglycemic drug, glimepiride (GLM) was studied in streptozotocin (STZ) induced diabetic rats. A specific and rapid HPLC-ESI-MS/MS method was established for simultaneous quantification of GLM and gymnemagenin (GMG) in rat plasma. Pharmacokinetic and pharmacodynamic interaction studies were carried out in STZ induced diabetic rats after concomitant administration of 400 mg/kg of G. sylvestre extract and 0.8 mg/kg of GLM for 28 days. The developed HPLC-ESI-MS/MS method was rapid, specific, and precise. Con-comitant oral administration of G. sylvestre extract (400 mg/kg) and GLM (0.8 mg/kg) in diabetic rats for 28 days showed beneficial pharmacodynamic interactions whereas no major alterations in the pharmacokinetics parameters of GLM and GMG were observed. This interaction demonstrated in animal model implies that significant clinical outcome might occur during concomitant administration of G. sylvestre extract and GLM especially in diabetic patients and warrants further studies in the same set up. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparison of Dapivirine Vaginal Gel and Film Formulation Pharmacokinetics and Pharmacodynamics (FAME 02B).

PubMed

Robinson, Jennifer A; Marzinke, Mark A; Bakshi, Rahul P; Fuchs, Edward J; Radebaugh, Christine L; Aung, Wutyi; Spiegel, Hans M L; Coleman, Jenell S; Rohan, Lisa C; Hendrix, Craig W

2017-04-01

While preexposure prophylaxis with oral tenofovir/emtricitabine reduces HIV acquisition rates, poor adherence to and acceptability of vaginal gels and the potential for evolving drug resistance have led to development of vaginal film formulations and other antiretroviral drugs, respectively, including the non-nucleoside reverse transcriptase inhibitor dapivirine. In this two-arm crossover study of a novel fast-dissolving dapivirine film and a previously studied semisolid dapivirine gel, 10 healthy women received a single 1.25 mg vaginal dose of each study product; one withdrew after the first dose. Clinical, pharmacokinetic, and antiviral pharmacodynamic assessments (ex vivo HIV-BaL challenge of tissue explants) were performed over 168 h postdose. Six of ten participants experienced mild to moderate adverse effects, similar between products, with no severe adverse events or adverse events attributed to study products. There were no statistically significant differences in plasma, cervicovaginal fluid (CVF), or cervical tissue dapivirine concentrations between the gel and film (all p > .05). CVF dapivirine concentrations were 1.5 and 6 log 10 greater than tissue and plasma concentrations, respectively (p < .001). Both film and gel demonstrated reduced cervical tissue infectivity after ex vivo HIV challenge 5 h postdose, compared to baseline and 72-h postdose biopsies (p < .05 for gel, p = .06 for film). There was no difference in ex vivo explant HIV challenge between gel and film. The dapivirine film and gel performed similarly in terms of tolerability, pharmacokinetics, and antiviral effect. Dapivirine film may provide an alternative to pharmacokinetically comparable dapivirine gel formulations. Effectiveness remains to be tested.

[Synthesis, biotransformation and pharmacodynamics of a new theophylline derivative].

PubMed

Oelschläger, H; Harsche, C; Engel, J

1991-09-01

7-[(RS)2-((S)-1-Methyl-2-phenyl-ethylamino)propyl]-theophylline (3) was not described until now. This fenetylline analogue is available by reaction of 7 with an excess of 2 at 150 degrees C. If 2 reacts with 4, an E2-elimination overwhelms SN-nucleophilic displacement yielding compound 5. In vivo studies with male White-Wistar rats, comparing biotransformation of 3 and 1, demonstrate, that the amount of 2 is decreased from 4.7% of (RS)-2 to 1%, probably due to steric hindrance of the attacking monooxygenases by the methyl group at C-11 of 3. Pharmacodynamic studies of 3, tested with mice, gave similar results to those obtained with 1.

Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women.

PubMed

Nel, Annalene M; Coplan, Paul; van de Wijgert, Janneke H; Kapiga, Saidi H; von Mollendorf, Claire; Geubbels, Eveline; Vyankandondera, Joseph; Rees, Helen V; Masenga, Gileard; Kiwelu, Ireen; Moyes, Jocelyn; Smythe, Shanique C

2009-07-31

To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.02%), and 28 used placebo gel twice daily for 42 days. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine. Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02% gel group on day 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less. Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

A study of safety and tolerability of rotatory vestibular input for preschool children

PubMed Central

Su, Wen-Ching; Lin, Chin-Kai; Chang, Shih-Chung

2015-01-01

The objectives of this study were to determine a safe rotatory vestibular stimulation input for preschool children and to study the effects of grade level and sex of preschool children during active, passive, clockwise, and counterclockwise rotation vestibular input. This study adopted purposive sampling with 120 children from three kindergarten levels (K1, K2, and K3) in Taiwan. The subjects ranged in age from 46 to 79 months of age (mean: 62.1 months; standard deviation =9.60). This study included testing with four types of vestibular rotations. The number, duration, and speed of rotations were recorded. The study found that the mean number of active rotations was 10.28; the mean duration of rotation was 24.17 seconds; and the mean speed was 2.29 seconds per rotation. The mean number of passive rotations was 23.04. The differences in number of rotations in clockwise, counterclockwise, active, and passive rotations were not statistically significant. Sex and grade level were not important related factors in the speed and time of active rotation. Different sexes, rotation methods (active, passive), and grades made significant differences in the number of rotations. The safety and tolerability of rotatory vestibular stimulation input data obtained in this study can provide useful reference data for therapists using sensory integration therapy. PMID:25657579

Performance and Safety of Lithium Ion Cells

NASA Technical Reports Server (NTRS)

Ratnakumar, B. V.; Smart, M. C.; Whitcanack, L.; Surampudi, S.; Marsh, R.

2001-01-01

This report evaluates the performance and safety of Lithium Ion (Li-Ion) cells when used in batteries. Issues discussed include the cycle life, energy efficiency, tolerance to higher charge voltage, tolerance to extended tapered charge voltage, charge on cycling, specific energy, low temperature discharge, low temperature charge, various charge characteristics, storage characteristics, and more of Li-Ion cells.

Applications of a damage tolerance analysis methodology in aircraft design and production

NASA Technical Reports Server (NTRS)

Woodward, M. R.; Owens, S. D.; Law, G. E.; Mignery, L. A.

1992-01-01

Objectives of customer mandated aircraft structural integrity initiatives in design are to guide material selection, to incorporate fracture resistant concepts in the design, to utilize damage tolerance based allowables and planned inspection procedures necessary to enhance the safety and reliability of manned flight vehicles. However, validated fracture analysis tools for composite structures are needed to accomplish these objectives in a timely and economical manner. This paper briefly describes the development, validation, and application of a damage tolerance methodology for composite airframe structures. A closed-form analysis code, entitled SUBLAM was developed to predict the critical biaxial strain state necessary to cause sublaminate buckling-induced delamination extension in an impact damaged composite laminate. An embedded elliptical delamination separating a thin sublaminate from a thick parent laminate is modelled. Predicted failure strains were correlated against a variety of experimental data that included results from compression after impact coupon and element tests. An integrated analysis package was developed to predict damage tolerance based margin-of-safety (MS) using NASTRAN generated loads and element information. Damage tolerance aspects of new concepts are quickly and cost-effectively determined without the need for excessive testing.

Pharmacokinetics/pharmacodynamics of levofloxacin 750 mg once daily in young women with acute uncomplicated pyelonephritis.

PubMed

Nicolle, Lindsay; Duckworth, Heather; Sitar, Dan; Bryski, Lisa; Harding, Godfrey; Zhanel, George

2008-03-01

This pilot study was undertaken to characterise the pharmacokinetics, pharmacodynamics and potential clinical efficacy of levofloxacin 750 mg once daily for 5 days for treatment of women with acute uncomplicated pyelonephritis. Four women diagnosed with acute pyelonephritis were enrolled. Following pre-therapy specimen collection, an initial oral dose of 750 mg levofloxacin was administered. The mean pharmacokinetic parameters for the first dose were: maximum serum concentration (C(max)) 12.5+/-4.7 mg/L (range 5.6-16.0mg/L) (fC(max) 8.8+/-3.3, where f indicates the levofloxacin free or non-protein-bound fraction), area under the serum concentration-time curve (AUC) 85.4+/-14.1 mgh/L (range 66.2-96.8 mgh/L) (fAUC 59.8+/-9.9) and serum half-life (t(1/2)) 6.7+/-0.5h. Mean urine concentrations were 88.0+/-100mg/L at the 0-3 h collection, 307+/-143 mg/L at 3-6 h, 170+/-107 mg/L at 6-12 h and 85+/-8 mg/L at 12-24 h. Mean levofloxacin serum pharmacodynamics for infecting Escherichia coli were: C(max)/minimum inhibitory concentration (MIC) 323+/-185(fC(max)/MIC 226+/-129); and AUC/MIC 2339+/-830(fAUC/MIC 1647+/-579). Mean urine levofloxacin concentration/MIC ratios were: 900+/-1389 for 0-3 h, 12100+/-4950 for 3-6 h, 5922+/-3912 for 6-12 h and 2233+/-1037 for 12-24 h. Levofloxacin eradicated E. coli from the urine by 3-6 h after the first dose. Levofloxacin 750 mg once daily for 5 days has pharmacodynamics that support further evaluation of this regimen for treatment of women with acute uncomplicated pyelonephritis.

Safety and tolerability of cell culture-derived and egg-derived trivalent influenza vaccines in 3 to <18-year-old children and adolescents at risk of influenza-related complications.

PubMed

Diez-Domingo, Javier; de Martino, Maurizio; Lopez, Jose Garcia-Sicilia; Zuccotti, Gian Vincenzo; Icardi, Giancarlo; Villani, Alberto; Moreno-Perez, David; Hernández, María Méndez; Aldeán, Javier Álvarez; Mateen, Ahmed Abdul; Enweonye, Igwebuike; de Rooij, Richard; Chandra, Richa

2016-08-01

This descriptive, non-comparative, phase III study evaluated the safety and tolerability of cell culture-derived (TIVc) and egg-derived (TIV) seasonal influenza vaccines in children at risk of influenza-related complications. Four hundred and thirty subjects were randomized 2:1 to TIVc or TIV. Subjects aged 3 to <9 years received one dose (if previously vaccinated, n=89) or two doses (if not previously vaccinated, n=124) of the study vaccines; the 9 to <18-year-olds (n=213) received one dose. Reactogenicity was assessed for 7 days after vaccination; safety was monitored for 6 months. After any vaccination, the most frequently reported solicited local adverse event (AE) was tenderness/pain (TIVc 44%, 66%, 53% and TIV 56%, 51%, 65% in the age groups 3 to <6 years, 6 to <9 years, and 9 to <18 years, respectively) and the systemic AE was irritability (22% TIVc, 24% TIV) in 3 to <6-year-olds and headache in 6 to <9-year-olds (20% TIVc, 13% TIV) and 9 to <18-year-olds (21% TIVc, 26% TIV). There were no cases of severe fever (≥40°C). No vaccine-related serious AEs were noted. New onset of chronic disease was reported in ≤1% of subjects. TIVc and TIV had acceptable tolerability and similar safety profiles in at-risk children (NCT01998477). Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Damage Tolerance Analysis of a Pressurized Liquid Oxygen Tank

NASA Technical Reports Server (NTRS)

Forth, Scott C.; Harvin, Stephen F.; Gregory, Peyton B.; Mason, Brian H.; Thompson, Joe E.; Hoffman, Eric K.

2006-01-01

A damage tolerance assessment was conducted of an 8,000 gallon pressurized Liquid Oxygen (LOX) tank. The LOX tank is constructed of a stainless steel pressure vessel enclosed by a thermal-insulating vacuum jacket. The vessel is pressurized to 2,250 psi with gaseous nitrogen resulting in both thermal and pressure stresses on the tank wall. Finite element analyses were performed on the tank to characterize the stresses from operation. Engineering material data was found from both the construction of the tank and the technical literature. An initial damage state was assumed based on records of a nondestructive inspection performed on the tank. The damage tolerance analyses were conducted using the NASGRO computer code. This paper contains the assumptions, and justifications, made for the input parameters to the damage tolerance analyses and the results of the damage tolerance analyses with a discussion on the operational safety of the LOX tank.

Understanding Risk Tolerance and Building an Effective Safety Culture

NASA Technical Reports Server (NTRS)

Loyd, David

2018-01-01

Estimates range from 65-90 percent of catastrophic mishaps are due to human error. NASA's human factors-related mishaps causes are estimated at approximately 75 percent. As much as we'd like to error-proof our work environment, even the most automated and complex technical endeavors require human interaction... and are vulnerable to human frailty. Industry and government are focusing not only on human factors integration into hazardous work environments, but also looking for practical approaches to cultivating a strong Safety Culture that diminishes risk. Industry and government organizations have recognized the value of monitoring leading indicators to identify potential risk vulnerabilities. NASA has adapted this approach to assess risk controls associated with hazardous, critical, and complex facilities. NASA's facility risk assessments integrate commercial loss control, OSHA (Occupational Safety and Health Administration) Process Safety, API (American Petroleum Institute) Performance Indicator Standard, and NASA Operational Readiness Inspection concepts to identify risk control vulnerabilities.

[Investigation on chromatogram-pharmacodynamics relationship of Angelica sinensis on effect of replenishing blood].

PubMed

Yang, Ying-Lai; Cui, Fang; Hu, Fang; Guo, Long; Yang, Tao; Li, Ying-Dong; Feng, Shi-Lan

2013-11-01

Blood deficiency model of mice was copied by subcutaneous injection with 200, 100 and 100 mg x kg(-1) (0.01 mL x g(-1)) acetyl phenylhydrazine (APH) at the frist, fourth, and seventh days. Mice in each group were perfused with different extracted parts of Angelica sinensis (drug dosage was 2.4 g x kg(-1)) at the tenth day, once a day for 10 days. Then compare the influence of different extracted parts of Angelica sinensis to RBC, Hb, PLT and thymus, spleen and weight changes of blood deficiency mice. The peak areas of each common peak from HPLC fingerprint were associated with the date of replenishing blood pharmacodynamics efficacy by using gray relation statistic, which was used to research the chromatogram-pharmacodynamics relationship. The results showed that the part of DSC has the better effect in replenishing blood. The contribution degree of the DSC to replenishing blood of each component were determined by correlation size, and ferulic acid made the largest contribution, but contribution of other components should not be ignored. In this paper, we research the relationship of the HPLC fingerprint and spectrum activity relationship, determine the material basis of the DSC for replenishing blood, and provide effective way to represent the spectral correlation effect.

Safety and Tolerability of Panax ginseng Root Extract: A Randomized, Placebo-Controlled, Clinical Trial in Healthy Korean Volunteers

PubMed Central

Lee, Nam-Hun; Yoo, Sa-Ra; Kim, Hyeong-Geug; Cho, Jung-Hyo

2012-01-01

Abstract Objectives Panax ginseng has been extensively used as an adaptogen and is among the top 10 selling herbal supplements in the United States over the past decade. However, there have been few reports about the toxicity of P. ginseng in human studies. Given the lack of toxicological studies in human, this study investigated whether P. ginseng administration causes any noticeable toxic effects in healthy volunteers. Methods This study was designed as a randomized, double-blind, placebo-controlled, and parallel group trial in healthy volunteers. The subjects were required to be healthy, free from any significant disease, as assessed at screening by physical examination, medical history, and laboratory (hematological and biochemical) tests. Eligible subjects received P. ginseng extract (1 g/day or 2 g/day) or placebo over a 4-week period. Results Although mild adverse events, such as dyspepsia, hot flash, insomnia, and constipation, were reported in both P. ginseng and placebo group, no serious untoward reactions were reported following P. ginseng administration. Nonsignificant changes were observed in hematological and biochemical tests. Conclusions P. ginseng administration for 4 weeks was shown to be safe, tolerable, and free of any untoward toxic effect in healthy male and female volunteers. Future results from ongoing multicenter collaborative efforts to evaluate short- and long-term effects of P. ginseng may contribute to our current understanding of safety and tolerability of this herbal product. PMID:22909282

Injury tolerance of tibia for the car-pedestrian impact.

PubMed

Mo, Fuhao; Arnoux, Pierre Jean; Jure, Jean Jaques; Masson, Catherine

2012-05-01

Lower limbs are normally the first contacted body region during car-pedestrian accidents, and easily suffer serious injuries. The previous tibia bending tolerances for pedestrian safety were mainly developed from three-point bending tests on tibia mid-shaft. The tibia tolerances of other locations are still not investigated enough. In addition, tibia loading condition under the car-pedestrian impact should be explored to compare with the three-point bending. This work aims to investigate the injury tolerance of tibia fracture with combined experimental data and numerical simulation. Eleven new reported quasi-static bending tests of tibia mid-shaft, and additional eleven dynamic mid-shaft bending test results in the previous literature were used to define injury risk functions. Furthermore, to investigate the influence of tibia locations on bending tolerance, finite element simulations with lower limb model were implemented according to three-point bending and pedestrian impact conditions. The regressive curve of tibia bending tolerance was obtained from the simulations on the different impact locations, and indicated that tibia fracture tolerance could vary largely due to the impact locations for the car-pedestrian crash. Copyright © 2011 Elsevier Ltd. All rights reserved.

A randomized, first-in-human, healthy volunteer trial of BIVV009, a humanized antibody for the specific inhibition of the classical complement pathway.

PubMed

Bartko, Johann; Schoergenhofer, Christian; Schwameis, Michael; Firbas, Christa; Beliveau, Martin; Chang, Colin; Marier, Jean-Francois; Nix, Darrell; Gilbert, James C; Panicker, Sandip; Jilma, Bernd

2018-05-08

Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease and warm autoimmune haemolytic anaemia. Therapeutic options for these complement-mediated disorders are limited and BIVV009, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase-1, first-in-human, double-blind, randomized, placebo-controlled, dose-escalation trial of single and multiple doses of BIVV009 or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles. Single and multiple infusions of BIVV009 were well tolerated without any safety concerns. BIVV009 exhibited a steep concentration-effect relationship with a Hill coefficient of 2.4, and an IC90 of 15.5 µg/mL. This study establishes the foundation for using BIVV009 as a highly selective inhibitor of the classical complement pathway in different diseases. This article is protected by copyright. All rights reserved. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures.

PubMed

Biton, Victor; Gil-Nagel, Antonio; Brodie, Martin J; Derossett, Sarah E; Nohria, Virinder

2013-11-01

Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; US adopted name) is an antiepileptic drug (AED) that prolongs neuronal voltage-gated potassium-channel KCNQ2-5 (Kv 7.2-7.5) opening. This double-blind study evaluated different RTG/EZG dose-titration rates. Patients (N=73) with partial-onset seizures receiving concomitant AEDs were randomized to one of three titration groups, all of which were initiated at RTG/EZG 300mg/day divided into three equal doses. Fast-, medium-, and slow-titration groups received dose increments of 150mg/day every 2, 4, and 7 days, respectively, achieving the target dose of 1200mg/day after 13, 25, and 43 days, respectively. Safety assessments were performed throughout. Discontinuation rates due to treatment-emergent adverse events (TEAEs) were numerically higher in the fast- (10/23) and medium- (7/22) titration groups than in the slow-titration group (3/23) but statistical significance was achieved only for the high-titration group compared with the low-titration group (p=0.024). Stratified analysis, with concomitant AEDs divided into enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) or noninducers, showed that the risk of discontinuation due primarily to TEAEs was significantly higher in the fast- (p=0.010) but not in the medium-titration group (p=0.078) when compared with the slow-titration group. Overall, the slow-titration rate appeared to be best tolerated and was used in further efficacy and safety studies with RTG/EZG. Copyright © 2013 Elsevier B.V. All rights reserved.

Progressive Fracture and Damage Tolerance of Composite Pressure Vessels

NASA Technical Reports Server (NTRS)

Chamis, Christos C.; Gotsis, Pascal K.; Minnetyan, Levon

1997-01-01

Structural performance (integrity, durability and damage tolerance) of fiber reinforced composite pressure vessels, designed for pressured shelters for planetary exploration, is investigated via computational simulation. An integrated computer code is utilized for the simulation of damage initiation, growth, and propagation under pressure. Aramid fibers are considered in a rubbery polymer matrix for the composite system. Effects of fiber orientation and fabrication defect/accidental damages are investigated with regard to the safety and durability of the shelter. Results show the viability of fiber reinforced pressure vessels as damage tolerant shelters for planetary colonization.

Effect of the cytochrome P450 2C19 inhibitor omeprazole on the pharmacokinetics and safety profile of bortezomib in patients with advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma.

PubMed

Quinn, David I; Nemunaitis, John; Fuloria, Jyotsna; Britten, Carolyn D; Gabrail, Nashat; Yee, Lorrin; Acharya, Milin; Chan, Kai; Cohen, Nadine; Dudov, Assen

2009-01-01

Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated. This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma, were aged >/=18 years, weighed >/=50 kg and had a life expectancy of >/=3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6-10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin version 4.0.1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay. Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively

Evaluation of Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild‐to‐Moderate Hypertension

PubMed Central

Langenickel, TH; Petruck, J; Kode, K; Ayalasomayajula, S; Schuehly, U; Greeley, M; Pal, P; Zhou, W; Prescott, MF; Sunkara, G; Rajman, I

2017-01-01

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open‐label, three‐period, single sequence study, patients with mild‐to‐moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (–5/–4/–4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470. PMID:28599060

HEMATOPOIETIC STEM CELL INFUSION/TRANSPLANTATION FOR INDUCTION OF ALLOGRAFT TOLERANCE

PubMed Central

Granados, Jose M. Marino; Benichou, Gilles; Kawai, Tatsuo

2015-01-01

Purpose of review This review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent findings Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Summary Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, as well as to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications. PMID:25563992

Antigen-Specific Tolerance in Immunotherapy of Th2-Associated Allergic Diseases

PubMed Central

Smarr, Charles B.; Bryce, Paul J.; Miller, Stephen D.

2013-01-01

Allergic diseases are an increasing health concern, particularly in the developed world. The standard clinical approach to treatment of allergic disease focuses on allergen avoidance and symptom control but does little to address the underlying Th2 bias of disease. Specific immunotherapy (SIT) consisting of controlled administration of allergen, however, has been demonstrated to successfully induce desensitization and tolerance in an antigen-specific manner for a variety of Th2-mediated diseases. This review focuses on the mechanisms by which current SIT approaches induce tolerance as well as discussing attempts to modify the safety and efficacy of SIT. These refinements focus on three major aspects of SIT: the route of antigen administration, modification of the antigen to remove allergenic epitopes and reduce adverse events and choice of adjuvant used to induce tolerance and/or immune deviation from Th2 to Th1 and regulatory T cell (Treg) phenotypes. Synthesis of these recent developments in SIT provides considerable promise for more robust therapies with improved safety profiles to improve resolution of allergic disease and its associated costs. PMID:24099300

Safety and Tolerability of Essential Oil from Cinnamomum zeylanicum Blume Leaves with Action on Oral Candidosis and Its Effect on the Physical Properties of the Acrylic Resin

PubMed Central

Oliveira, Julyana de Araújo; da Silva, Ingrid Carla Guedes; Trindade, Leonardo Antunes; Lima, Edeltrudes Oliveira; Carlo, Hugo Lemes; Cavalcanti, Alessandro Leite; de Castro, Ricardo Dias

2014-01-01

The anti-Candida activity of essential oil from Cinnamomum zeylanicum Blume, as well as its effect on the roughness and hardness of the acrylic resin used in dental prostheses, was assessed. The safety and tolerability of the test product were assessed through a phase I clinical trial involving users of removable dentures. Minimum inhibitory concentration (MIC) and minimum fungicidal concentrations (MFC) were determined against twelve Candida strains. Acrylic resin specimens were exposed to artificial saliva (GI), C. zeylanicum (GII), and nystatin (GIII) for 15 days. Data were submitted to ANOVA and Tukey posttest (α = 5%). For the phase I clinical trial, 15 healthy patients used solution of C. zeylanicum at MIC (15 days, 3 times a day) and were submitted to clinical and mycological examinations. C. zeylanicum showed anti-Candida activity, with MIC = 625.0 µg/mL being equivalent to MFC. Nystatin caused greater increase in roughness and decreased the hardness of the material (P < 0.0001), with no significant differences between GI and GII. As regards the clinical trial, no adverse clinical signs were observed after intervention. The substance tested had a satisfactory level of safety and tolerability, supporting new advances involving the clinical use of essential oil from C. zeylanicum. PMID:25574178

Development of acute tolerance to the EEG effect of propofol in rats.

PubMed

Ihmsen, H; Schywalsky, M; Tzabazis, A; Schwilden, H

2005-09-01

A previous study in rats with propofol suggested the development of acute tolerance to the EEG effect. The aim of this study was to evaluate acute tolerance by means of EEG-controlled closed-loop anaesthesia as this approach allows precise determination of drug requirement to maintain a defined drug effect. Ten male Sprague-Dawley rats [weight 402 (40) g, mean (SD)] were included in the study. The EEG was recorded with occipito-occipital needle electrodes and a modified median frequency (mMEF) of the EEG power spectrum was used as a pharmacodynamic control parameter. The propofol infusion rate was controlled by a model-based adaptive algorithm to maintain a set point of mMEF=3 (0.5) Hz for 90 min. The performance of the closed-loop system was characterized by the prediction error PE=(mMEF-set point)/set point. Plasma propofol concentrations were determined from arterial samples by HPLC. The chosen set point was successfully maintained in all rats. The median (SE) and absolute median values of PE were -5.0 (0.3) and 11.3 (0.2)% respectively. Propofol concentration increased significantly from 2.9 (2.2) microg ml(-1) at the beginning to 5.8 (3.8) microg ml(-1) at 90 min [mean (SD), P<0.05]. The cumulative dose increased linearly, with a mean infusion rate of 0.60 (0.16) mg kg(-1) min(-1). The minimum value of the mean arterial pressure during closed-loop administration of propofol was 130 (24) mm Hg, compared with a baseline value of 141 (12) mm Hg. The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.

Development and validation of receptor occupancy pharmacodynamic assays used in the clinical development of the monoclonal antibody vedolizumab.

PubMed

Wyant, Tim; Estevam, Jose; Yang, Lili; Rosario, Maria

2016-03-01

Vedolizumab is a monoclonal antibody approved for use in ulcerative colitis and Crohn's disease. By specifically binding to α4 β7 integrin, vedolizumab prevents trafficking of lymphocytes to the gut, thereby interfering with disease pathology. During the clinical development program, the pharmacodynamic effect of vedolizumab was evaluated by 2 flow cytometry receptor occupancy assays: act-1 (ACT-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Here we describe the development and validation of these assays. The ACT-1 assay is a receptor occupancy free-site assay that uses a monoclonal antibody with the same binding epitope as vedolizumab to detect free (unbound) sites on α4 β7 integrin. The MAdCAM-1 assay used a soluble version of the natural ligand for α4 β7 integrin to detect free sites. The assays were validated using a fit-for-purpose approach throughout the clinical development of vedolizumab. Both the ACT-1 assay and the MAdCAM-1 assay demonstrated acceptable reproducibility and repeatability. The assays were sufficiently stable to allow for clinical use. During clinical testing the assays demonstrated that vedolizumab was able to saturate peripheral cells at all doses tested. Two pharmacodynamic receptor occupancy assays were developed and validated to assess the effect of vedolizumab on peripheral blood cells. The results of these assays demonstrated the practical use of flow cytometry to examine pharmacodynamic response in clinical trials. © 2015 International Clinical Cytometry Society.

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

PubMed Central

Ricotti, Valeria; Spinty, Stefan; Roper, Helen; Hughes, Imelda; Tejura, Bina; Robinson, Neil; Layton, Gary; Davies, Kay

2016-01-01

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511 PMID:27055247

Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog.

PubMed

Jeunesse, Elisabeth C; Schneider, Marc; Woehrle, Frederique; Faucher, Mathieu; Lefebvre, Herve P; Toutain, Pierre-Louis

2013-12-11

Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin-induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model). Analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs.For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD).The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 μg/L for creeping speed, 284 μg/L for the lameness score, 161 μg/L for the ground reaction vertical force and 193 μg/L for the body temperature.To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg

Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine.

PubMed

Cysneiros, R M; Farkas, D; Harmatz, J S; von Moltke, L L; Greenblatt, D J

2007-07-01

The kinetic and dynamic interaction of caffeine and zolpidem was evaluated in a double-blind, single-dose, six-way crossover study of 7.5 mg zolpidem (Z) or placebo (P) combined with low-dose caffeine (250 mg), high-dose caffeine (500 mg), or placebo. Caffeine coadministration modestly increased maximum plasma concentration (C(max)) and area under the plasma concentration-time curve of zolpidem by 30-40%, whereas zolpidem did not significantly affect the pharmacokinetics of caffeine or its metabolites. Compared to P+P, Z+P significantly increased sedation, impaired digit-symbol substitution test performance, slowed tapping speed and reaction time, increased EEG relative beta amplitude, and impaired delayed recall. Caffeine partially, but not completely, reversed most pharmacodynamic effects of zolpidem. Thus, caffeine only incompletely reverses zolpidem's sedative and performance-impairing effects, and cannot be considered as an antidote to benzodiazepine agonists.

Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial

PubMed Central

Tarcha, Eric J.; Probst, Peter; Peckham, David; Muñoz-Elías, Ernesto J.; Kruger, James G.; Iadonato, Shawn P.

2017-01-01

Background Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis. Objective The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations. Methods Patients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires. Results The most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells. Limitations The study was small and drug treatment was for a short duration (4 weeks). Conclusion This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted. PMID:28723914

Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

PubMed

Nations, Kari R; Dogterom, Peter; Bursi, Roberta; Schipper, Jacques; Greenwald, Scott; Zraket, David; Gertsik, Lev; Johnstone, Jack; Lee, Allen; Pande, Yogesh; Ruigt, Ge; Ereshefsky, Larry

2012-12-01

Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.

Safety, tolerability and efficacy of intradermal rabies immunization with DebioJect™.

PubMed

Vescovo, Paul; Rettby, Nils; Ramaniraka, Nirinarilala; Liberman, Julie; Hart, Karen; Cachemaille, Astrid; Piveteau, Laurent-Dominique; Zanoni, Reto; Bart, Pierre-Alexandre; Pantaleo, Giuseppe

2017-03-27

In a single-center study, 66 healthy volunteers aged between 18 and 50years were randomized to be immunized against rabies with three different injection routes: intradermal with DebioJect™ (IDJ), standard intradermal with classical needle (IDS), also called Mantoux method, and intramuscular with classical needle (IM). "Vaccin rabique Pasteur®" and saline solution (NaCl 0.9%) were administered at D0, D7 and D28. Antigen doses for both intradermal routes were 1/5 of the dose for IM. Tolerability, safety and induced immunogenicity of IDJ were compared to IDS and IM routes. Pain was evaluated at needle insertion and at product injection for all vaccination visits. Solicited Adverse Event (SolAE) and local reactogenicity symptoms including pain, redness and pruritus were recorded daily following each vaccination visit. Adverse events (AE) were recorded over the whole duration of the study. Humoral immune response was measured by assessing the rabies virus neutralizing antibody (VNA) titers using Rapid Fluorescent Focus Inhibition Test (RFFIT). Results demonstrated that the DebioJect™ is a safe, reliable and efficient device. Significant decreases of pain at needle insertion and at vaccine injection were reported with IDJ compared to IDS and IM. All local reactogenicity symptoms (pain, redness and pruritus) after injection with either vaccine or saline solution, were similar for IDJ and IDS, except that IDJ injection induced more redness 30min after saline solution. No systemic SolAE was deemed related to DebioJect™ and classical needles. No AE was deemed related to DebioJect™. No Serious Adverse Event (SAE) was reported during the study. At the end of the study all participants were considered immunized against rabies and no significant difference in humoral response was observed between the 3 studied routes. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES

EPA Science Inventory

Physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) models are particularly suited for interpretation of cumulative risk via the dermal route for which aggregate exposure must be assessed for chemicals having a common mechanism of toxicity. To this end, a quantita...

Safety and tolerability of intrathecal liposomal cytarabine as central nervous system prophylaxis in patients with acute lymphoblastic leukemia.

PubMed

Valentin, Angelika; Troppan, Katharina; Pfeilstöcker, Michael; Nösslinger, Thomas; Linkesch, Werner; Neumeister, Peter

2014-08-01

Central nervous system recurrence in acute lymphoblastic leukemia (ALL) occurs in up to 15% of patients and is frequently associated with poor outcome. The purpose of our study was to evaluate the efficacy and safety of a slow-release liposomal formulation of cytarabine for intrathecal (IT) meningeal prophylaxis in patients suffering from ALL. Forty patients aged 20-77 years (median 36) were preventively treated with a total of 96 (range 1-6) single doses containing 50 mg of liposomal cytarabine on a compassionate use basis. After a median observation period of 23 months (range 2-118) only two patients experienced a combined medullary-leptomeningeal disease recurrence after primary diagnosis. Except for headache grade 2 in two patients, no specific toxicity attributable to IT liposomal cytarabine application was noted. Long-term neurological side effects were not observed. IT liposomal cytarabine therapy with concomitant dexamethasone appears to be feasible and well tolerated.

Simulation of a G-tolerance curve using the pulsatile cardiovascular model

NASA Technical Reports Server (NTRS)

Solomon, M.; Srinivasan, R.

1985-01-01

A computer simulation study, performed to assess the ability of the cardiovascular model to reproduce the G tolerance curve (G level versus tolerance time) is reported. A composite strength duration curve derived from experimental data obtained in human centrifugation studies was used for comparison. The effects of abolishing automomic control and of blood volume loss on G tolerance were also simulated. The results provide additional validation of the model. The need for the presence of autonomic reflexes even at low levels of G is pointed out. The low margin of safety with a loss of blood volume indicated by the simulation results underscores the necessity for protective measures during Shuttle reentry.

Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus

PubMed Central

2011-01-01

Background The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA. Methods 40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 106 and 108 cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model. Results 15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 106 cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 108 cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log10 CFU/ml for agr functional vs. 2.41 log10 CFU/ml for agr dysfunctional MRSA (p = 0.0007). Conclusions Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections. PMID:21599878

Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus.

PubMed

Tsuji, Brian T; MacLean, Robert D; Dresser, Linda D; McGavin, Martin J; Simor, Andrew E

2011-05-20

The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA. 40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 10(6) and 10(8) cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model. 15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 10(6) cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 10(8) cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log(10) CFU/ml for agr functional vs. 2.41 log(10) CFU/ml for agr dysfunctional MRSA (p = 0.0007). Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections.

Population pharmacokinetics and pharmacodynamics of fosfomycin in non-critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli.

PubMed

Merino-Bohórquez, V; Docobo-Pérez, F; Sojo, J; Morales, I; Lupión, C; Martín, D; Cameán, M; Hope, W; Pascual, Á; Rodríguez-Baño, J

2018-04-10

To describe the population pharmacokinetics of fosfomycin for patients with bacteraemic urinary tract infection (BUTI). The analysis identified optimal regimens on the basis of pharmacodynamic targets and assessed the adequacy of Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoints for Escherichia coli. Data of 16 patients with BUTI caused by multidrug-resistant E. coli (FOREST clinical trial) received intravenous fosfomycin (4 g every 6 hours) were analysed. A population pharmacokinetic analysis was performed, and Monte Carlo simulations were undertaken using 4 g every 6 hours and 8 g every 8 hours. The probability of pharmacodynamic target attainment was assessed using pharmacodynamic targets for E. coli for static effect, 1-log drop in bacterial burden and resistance suppression. Sixty-four plasma samples were collected over a single dosing interval (day 2 or 3 after starting fosfomycin treatment). Fosfomycin concentrations were highly variable. Pharmacodynamic target attainment analysis showed mild improvement by increasing fosfomycin dosing (4 g every 6 hours vs. every 8 hours). These dosages showed success for decreasing 1-log bacterial burden in 89% to 96% (EUCAST breakpoints) and 33% to 54% (CLSI breakpoints) of patients, but they were unable to reach bacterial resistance suppression targets. Fosfomycin concentrations are highly variable-a fact partially explained by renal impairment. The present work supports the use of 4 g every 6 hours as an effective regimen for the treatment of non-critically ill patients with BUTI caused by multidrug-resistant E. coli, as higher dosages might increase toxicity but may not significantly increase efficacy. The current information may suggest that fosfomycin susceptibility breakpoints need to be reappraised. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by

Results of a Phase 2, Randomized,Vehicle-Controlled Study Evaluating the Efficacy,Tolerability, and Safety of Daily or Twice Daily SB204 for the Treatment of Acne Vulgaris.

PubMed

Eichenfield, Lawrence F; Gold, Linda Stein; Nahm, Walter K; Cook-Bolden, Fran E; Pariser, David M

2016-12-01

This randomized, double-blind, placebo-controlled, Phase 2 study compared efficacy, tolerability, and safety of SB204 once or twice daily to vehicle in the treatment of acne vulgaris. Eligible subjects were to be between 12 and 40 years old, have facial acne vulgaris with 25 to 70 non-inflammatory lesions, 20 to 40 inflammatory lesions, no more than 2 nodules, and a baseline Investigator's Global Assessment (IGA) score of moderate or severe. The co-primary efficacy endpoints were the absolute change in inflammatory and non-inflammatory lesion counts and IGA success rate (baseline to week 12). Safety assessments included reported adverse events (AEs), physical examinations, and laboratory testing. Tolerability was evaluated by the investigators based on the occurrence and severity of erythema, scaling, dryness, pruritus, and burning/stinging. A total of 213 subjects were randomized: 27 subjects to vehicle once daily; 29 subjects to vehicle twice daily; 53 subjects to SB204 2% twice daily; 52 subjects to SB204 4% once daily; and 52 subjects to SB204 4% twice daily. When compared to vehicle, treatment with all 3 SB204 regimens significantly reduced the absolute inflammatory lesion count and SB204 4% once daily reduced the absolute non-inflammatory lesion count. Treatment with SB204 4% once daily demonstrated a significant reduction in percent inflammatory lesions by week 4. There were no significant differences in the IGA success rates between groups at the end of treatment. All treatment regimens of SB204 were found to be safe and well tolerated. When compared to vehicle, SB204 2% and SB204 4% significantly decreased the absolute inflammatory lesion count and SB204 4% once daily also significantly decreased the absolute non-inflammatory lesion count in subjects with acne vulgaris treated for 12 weeks. Treatment with SB204 2% and 4% was found to be safe and well tolerated. J Drugs Dermatol. 2016;15(12):1496-1502.

Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration.

PubMed

Yang, Zhen-Zhen; Zhang, Yan-Qing; Wang, Zhan-Zhang; Wu, Kai; Lou, Jin-Ning; Qi, Xian-Rong

2013-08-16

Alzheimer's disease (AD) is a common progressive neurodegenerative disorder associated with cholinergic neurons degeneration. The blood-brain barrier (BBB) not only provides protection for the brain but also hinders the treatment and diagnosis of this neurological disease, because the drugs must cross BBB to reach the lesions. The present work was aimed at formulating rivastigmine liposomes (Lp) and cell-penetrating peptide (CPP) modified liposomes (CPP-Lp) to improve rivastigmine distribution in brain and proceed to enhance pharmacodynamics by intranasal (IN) administration and minimize side effects. The results revealed that Lp especially the CPP-Lp can enhance the permeability across the BBB by murine brain microvascular endothelial cells model in vitro. IN administration of rivastigmine solution and rivastigmine liposomes demonstrated the capacity to improve rivastigmine distribution and adequate retention in CNS regions especially in hippocampus and cortex, which were the regions most affected by AD, than that of IV administration. Importantly, the lagging but intense inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities were relative to the extended release, absorption and retention. In addition, there was very mild nasal toxicity of liposomal formulations. The data suggest that rivastigmine liposomes especially CPP-Lp improve the brain delivery and enhance pharmacodynamics which respect to BBB penetration and nasal olfactory pathway into brain after IN administration, and simultaneously decrease the hepatic first pass metabolism and gastrointestinal adverse effects. Copyright © 2013 Elsevier B.V. All rights reserved.

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glargine 300 U/mL.

PubMed

Clements, Jennifer N; Threatt, Tiffaney; Ward, Eileen; Shealy, Kayce M

2017-05-01

Concentrated insulin analogs have recently been approved and are available for clinical use in the management of diabetes mellitus. One new product is insulin glargine U-300 (Sanofi), a basal concentrated insulin of 300 U/mL. Several studies have been conducted and completed evaluating blood samples for the pharmacokinetics of insulin glargine U-300 and euglycemic clamp procedures for the pharmacodynamics. This concentrated insulin has a low within-day variability and high day-to-day reproducibility, allowing for a more constant and prolonged duration of action, compared with insulin glargine U-100 (100 U/mL). Insulin glargine U-300 is equally effective, when compared with insulin glargine U-100 for glycemic control in patients with type 1 and 2 diabetes mellitus. Insulin glargine U-300 has a similar efficacy profile to insulin glargine U-100 for glycemic control, yet with lower rates of nocturnal and severe hypoglycemia. Insulin glargine U-300 can be considered an acceptable basal insulin for patients with type 1 and 2 diabetes mellitus, and it has a potential role among patients who are naïve to insulin therapy or require titration of basal insulin. Titration of insulin glargine U-300 would result in less volume and a lower risk of hypoglycemia, compared with insulin glargine U-100. This article evaluates and summarizes the pharmacokinetics and pharmacodynamics of insulin glargine U-300, for patients with type 1 or 2 diabetes mellitus, and summarizes its application to clinical practice.

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study.

PubMed

DeLemos, Byron; Richards, Henry M; Vandenbossche, Joris; Ariyawansa, Jay; Natarajan, Jaya; Alexander, Binu; Ramakrishna, Tage; Murtaugh, Thomas; Stahlberg, Hans-Jürgen

2017-11-01

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUC tau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400  and 600 mg/day, whereas the C max,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study. © 2017, The American College of Clinical Pharmacology.