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Sample records for evaluate pharmacokinetics safety

  1. Pharmacokinetics and preliminary safety evaluation of azithromycin in adult horses.

    PubMed

    Leclere, M; Magdesian, K G; Cole, C A; Szabo, N J; Ruby, R E; Rhodes, D M; Edman, J; Vale, A; Wilson, W D; Tell, L A

    2012-12-01

    Azithromycin is widely used in foals but has not been studied in adult horses. The goals of this study were to determine the pharmacokinetic profile and to make a preliminary assessment of the safety of azithromycin in adult horses. Azithromycin was administered intravenously (5 mg/kg) and intragastrically (10 mg/kg) to six healthy mares in a crossover design. Serial plasma samples, blood neutrophils, and pulmonary macrophages were collected for the measurement of azithromycin concentrations. Azithromycin was also administered orally (10 mg/kg) once a day for 5 days to five healthy mares for preliminary evaluation of safety in adult horses. The bioavailability of azithromycin following intragastric administration was 45 ± 12%. Concentrations within peripheral neutrophils and bronchoalveolar macrophages were several fold higher than that of plasma. Mild decreases in appetite (n = 3) and alterations in fecal consistency (n = 3) were noted following repeated oral administration. The pharmacokinetic profiles of azithromycin in adult horses, especially the slow elimination rate and intraneutrophil and intrapulmonary macrophage accumulation, demonstrate that it is conducive to use in this age group. Because of the gastrointestinal alterations noted, further studies are warranted before azithromycin can be recommended for use in adult horses.

  2. FRAMEWORK FOR EVALUATION OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELS FOR USE IN SAFETY OR RISK ASSESSMENT

    EPA Science Inventory

    ABSTRACT

    Proposed applications of increasingly sophisticated biologically-based computational models, such as physiologically-based pharmacokinetic (PBPK) models, raise the issue of how to evaluate whether the models are adequate for proposed uses including safety or risk ...

  3. FRAMEWORK FOR EVALUATION OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELS FOR USE IN SAFETY OR RISK ASSESSMENT

    EPA Science Inventory

    ABSTRACT

    Proposed applications of increasingly sophisticated biologically-based computational models, such as physiologically-based pharmacokinetic (PBPK) models, raise the issue of how to evaluate whether the models are adequate for proposed uses including safety or risk ...

  4. The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

    PubMed Central

    Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-01-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. PMID:25845860

  5. 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

  6. 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.

  7. 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

  8. Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses.

    PubMed Central

    Barbhaiya, R H; Forgue, S T; Gleason, C R; Knupp, C A; Pittman, K A; Weidler, D J; Martin, R R

    1990-01-01

    In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime. PMID:2203303

  9. Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers.

    PubMed

    Belmonte, Carmen; Ochoa, Dolores; Román, Manuel; Cabaleiro, Teresa; Talegón, Maria; Sánchez-Rojas, Sergio Daniel; Abad-Santos, Francisco

    2016-12-01

    The aim of this study was the evaluation of the possible relationship between pharmacokinetics and the safety of aripiprazole as well as its influence on blood pressure (BP), heart rate (HR), and corrected QT (QTc) interval. The study population comprised 157 healthy volunteers from 6 bioequivalence clinical trials. Subjects were administered a single 10-mg oral dose of each formulation separated by a 28-day washout period. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Blood pressure was measured at the following times: predose and 0.5, 2, 4, 6, and 8 hours postdose. An electrocardiogram was recorded at predose, 4, and 8 hours postdose. Area under the curve (AUC), maximum plasma concentration, half-life, and distribution volume corrected for weight were higher in women. Aripiprazole treatment produced a decrease of BP (9.3 mm Hg on systolic and 6.2 mm Hg on diastolic pressure) and an increase in HR (12.1 beats per minute) and QTc interval (9.1 milliseconds). There were sex differences in BP, HR, and QTc interval. Women and subjects with higher AUC and maximum plasma concentration values were more prone to experience adverse drug reactions and gastrointestinal adverse reactions. The AUC was related with systolic BP and diastolic BP decrease and HR increase but there was no relationship between aripiprazole concentrations and QTc increase. Aripiprazole decreases BP and increases HR and QTc interval. Pharmacokinetics, pharmacodynamics, and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and adverse drug reactions and effect on BP and HR.

  10. The pharmacokinetics of phenylethyl alcohol (PEA): safety evaluation comparisons in rats, rabbits, and humans.

    PubMed

    Politano, Valerie T; Diener, Robert M; Christian, Mildred S; Hawkins, David R; Ritacco, Gretchen; Api, Anne Marie

    2013-01-01

    The present studies were conducted to compare the dermal absorption, plasma pharmacokinetics, and excretion of phenylethyl alcohol (PEA) by pregnant and nonpregnant rats, rabbits, and humans. The PEA is a natural fragrance material that is widely used in perfumes, soaps, and lotions and is a major ingredient of natural rose oil. Following dermal (430, 700, or 1400 mg/kg body weight [bw]), gavage (430 mg/kg bw), or dietary (430 mg/kg bw) administration of PEA to rats, plasma concentrations of PEA were found to be low regardless of the route of administration. The plasma concentrations of phenylacetic acid (PAA, the major metabolite of PEA) greatly exceeded the concentrations of PEA and were highest after gavage, followed by dermal then dietary administration. Absorption, distribution, metabolism, and excretion were compared following topical application of ¹⁴C-labeled PEA to rats, rabbits, and humans (specific activities of dosing solutions: 58-580, 164, and 50 µCi/mL, respectively). In rabbits, the plasma concentration-time profile for PAA was markedly prolonged compared to rats or humans. In humans, only 7.6% of the applied dose of PEA was absorbed, versus 77% in rats and 50% in rabbits. Based on a human dermal systemic exposure of 0.3 mg/kg per day from the use of multiple consumer personal care products containing PEA, a rat dermal no observed adverse effect level of 70 mg/kg per day, and the percentage of dose absorbed in humans, the margin of safety exceeds 2600 concluding that, under normal fragrance use conditions, PEA is not a developmental toxicity hazard for humans.

  11. Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma

    PubMed Central

    2013-01-01

    Background Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma. Methods Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin. Results Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 μM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone

  12. Evaluation of Herbal Medicines: Value Addition to Traditional Medicines Through Metabolism, Pharmacokinetic and Safety Studies.

    PubMed

    Thelingwani, Roslyn; Masimirembwa, Collen

    2014-01-01

    The safety and efficacy of herbal medicines remain major issues of concern especially in the developing world where the use is high. The World Health Organisation estimates up to 80% of the population in Africa relies on herbal medicines for treatment of many diseases. Minimum safety evaluations need to be done for both the herbal and conventional drugs, in particular when there is a high likelihood of co-administration. This is particularly important in Africa where there is increased access to antiretrovirals in the treatment of HIV/AIDS, which are being used in a population background characterized by rampant use of herbal medicines. Many techniques used in the discovery and evaluation of conventional drugs can be adapted to herbal medicines. Such evaluations will add value to herbal medicines as doctors and patients will be better informed on which drugs and herbal medicines to take or not take together. This can also lead to the adoption of guidelines by regulatory agents such as the European Medicines Agency (EMA), Food and Drug Administration (FDA) and governmental agencies controlling the use of medicines. Of current interest is the evaluation of drug-herb interactions (DHI) involving the absorption, distribution, metabolism and excretion (ADME) of medicines where there is a promising possibility to adopt the current FDA and EMA guidelines on the evaluation of herbal medicines for drug-drug interactions (DDI). In this review we demonstrate progress made so far in DHI and point to possible future developments that will contribute to the safe use of herbal medicines.

  13. Pharmacokinetic and safety evaluation of the use of ciprofloxacin on an isoniazid-rifampicin regimen in rabbits.

    PubMed

    Padilha, Elias Carvalho; Pires, Rodrigo Vieira; Filho, Marco Antonio Ferraz Nogueira; de Pontes Machado, Diego Vinicius; Baldan, Helen Mariana; Davanço, Marcelo Gomes; Campos, Michel Leandro; Brunetti, Iguatemy Lourenço; Peccinini, Rosângela Gonçalves

    2012-12-01

    The combination of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) is used in the treatment of tuberculosis. Although this treatment is effective in most clinical cases, the side-effects and the development of mycobacterium resistance have hindered its success. There is evidence that the combination of INH, RMP and ciprofloxacin (CIPRO) is useful in the treatment of tuberculosis. However, the influence of this drug combination on the hepatotoxicity of INH is unknown. In this study, the safety of combined INH, RMP and CIPRO was evaluated. Male albino rabbits (n = 20) were divided into four groups and subjected to multiple oral doses for 7 days according to the following treatments: water (group 1); 50 mg/kg INH (group 2); 50 mg/kg INH + 100 mg/kg RMP (group 3) and 50 mg/kg INH + 100 mg/kg RMP + 50 mg/kg CIPRO (group 4). Blood samples were taken before and after treatments for the determination of ALT, AST, ALP and bilirubin to assess hepatotoxicity. For pharmacokinetic analysis, serial blood samples were collected over 24 h on day 7 of treatment. Plasma concentrations of INH and acetylisoniazid (AcINH) were determined by HPLC. Biochemical parameters did not show any statistically significant differences between the groups that received the drug combinations. The pharmacokinetic profile of INH was also similar for both groups of combinations. These findings allow us to infer that the inclusion of CIPRO did not increase the risk of hepatotoxicity when compared with the classic combination of INH and RMP.

  14. Pharmacokinetic evaluation of frovatriptan.

    PubMed

    Negro, Andrea; Lionetto, Luana; Casolla, Barbara; Lala, Noemi; Simmaco, Maurizio; Martelletti, Paolo

    2011-11-01

    Migraine is the most common painful neurological disorder, affecting 13% of the general population. Triptans represent a powerful pharmacological tool in acute migraine treatment, however, a significant portion of treated patients cannot have access to this class due to possible adverse affects. Today, a total of seven triptan molecules are available, representing a commonly prescribed migraine treatment. Although there is a need of extensive use of triptans, only 25% of migraine patients are using triptans. This review includes triptans and evidence for the use of frovatriptan. A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan, considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches. The data were obtained by searching the following key words in MEDLINE: pharmacokinetic, pharmacodynamic, triptans, frovatriptan, migraine, menstrual migraine, relatively to the period 1988 - 2011. Frovatriptan has been developed in order to improve safety and efficacy of triptans. It shows a favorable tolerability and efficacy profile, limited to 24/48-h headache recurrence, when compared with other triptans. Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans. In fact, among triptans, frovatriptan showed the highest potency at the 5-HT1B receptor (8.2) and the longer half-life (26 h). These parameters determine the clinical properties of frovatriptan; in particular the lowest rate of headache recurrence in comparison with other triptans.

  15. Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects.

    PubMed

    Abbas, Richat; Chalon, Stephan; Leister, Cathie; El Gaaloul, Myriam; Sonnichsen, Daryl

    2013-01-01

    Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Hepatically impaired patients were aged 18-65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast. Compared with healthy subjects (n = 9), maximal plasma concentration (C(max)) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C(max) decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0%, n = 10), nausea (11.1%, n = 3), and vomiting (7.4%, n = 2). A single oral dose of bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.

  16. Phase I Combination of Sorafenib and Erlotinib Therapy in Solid Tumors: Safety, Pharmacokinetic and Pharmacodynamic Evaluation from an Expansion Cohort

    PubMed Central

    Quintela-Fandino, Miguel; Le Tourneau, Christophe; Duran, Ignacio; Chen, Eric X.; Wang, Lisa; Tsao, Ming; Bandarchi-Chamkhaleh, Bizhan; Pham, Nhu-Ann; Do, Trevor; MacLean, Martha; Nayyar, Rakesh; Tusche, Michael W.; Metser, Ur; Wright, John J.; Mak, Tak W.; Siu, Lillian L.

    2010-01-01

    The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic (PK) and pharmacodynamic (PD) markers with clinical outcome. In addition, a novel PD marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a one-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. EGFR expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pre-treatment, prior to erlotinib dosing and during the administration of both drugs. In addition, PET-CT scans and PK assessments were performed. Eleven patients received a total of 57 cycles (median: 5, range: 1–10). Only 4 patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of 4 or more cycles. PK analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in 7 patients. Other PD markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib. PMID:20197396

  17. Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

    NASA Astrophysics Data System (ADS)

    Cekanova, Maria; Uddin, Md. Jashim; Legendre, Alfred M.; Galyon, Gina; Bartges, Joseph W.; Callens, Amanda; Martin-Jimenez, Tomas; Marnett, Lawrence J.

    2012-11-01

    We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg/kg showed a peak of fluorocoxib A (92±28 ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

  18. Non-clinical safety and pharmacokinetic evaluations of propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs.

    PubMed

    Werley, Michael S; McDonald, Paddy; Lilly, Patrick; Kirkpatrick, Daniel; Wallery, Jeffrey; Byron, Peter; Venitz, Jürgen

    2011-09-05

    Aerosolized propylene glycol (PG) was generated as log-normally distributed particulate clouds in different concentrations using a novel capillary aerosol generator (CAG) and evaluated in a battery of non-clinical studies intended to assess its potential inhalation and systemic toxicity in 2 species before ICH-compliant "first-time-in-man" studies. Exposures were nose-only in rats, and via face mask with oropharyngeal tube in dogs. The CAG-generated PG aerosol had a mass median aerodynamic diameter (MMAD) of 2.29μm, with a 1.56 geometric standard deviation (GSD) in the rat studies, and a MMAD of 1.34μm (1.45 GSD) in the dog studies, consistent with expected particle size exposures in man. International Congress on Harmonization (ICH) Guidelines were followed, which recommend preliminary non-clinical safety studies using the vehicle and device (CAG-PG) prior to the first human exposure including safety pharmacology, pharmacokinetic (PK) studies, single dose toxicity studies, and repeated dose toxicity studies in two species. In the rat, the only biologically relevant findings included clinical signs of ocular and nasal irritation indicated by minor bleeding around the eyes and nose, and minimal laryngeal squamous metaplasia. This finding is commonly observed in inhalation studies in the rat, and likely related to the unique sensitivity of the tissue, as well as the circuitous airflow pathway through the larynx which increases particle deposition. In the female Beagle dog, treatment-related decreases in hemoglobin, red blood cells and hematocrit were observed in the two highest exposure groups, equivalent to approximately 18 and 60mg/kg/day. In male dogs from the high dose group, similar small decreases, albeit, non-statistically significant decreases were observed in these hematological markers as well. PK studies in rats and dogs showed that the absorption of PG following pulmonary inhalation exposure occurs rapidly, and equilibrium between lung tissue and plasma

  19. Pharmacokinetic and Safety Evaluation of BILR 355, a Second-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers▿

    PubMed Central

    Huang, Fenglei; Koenen-Bergmann, Michael; MacGregor, Thomas R.; Ring, Arne; Hattox, Susan; Robinson, Patrick

    2008-01-01

    BILR 355 is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) under clinical development for the treatment of human immunodeficiency virus infection, particularly in those who harbor virus resistant to the currently available NNRTIs. Two single-center, double-blinded, placebo-controlled, parallel dose-escalation studies were conducted to evaluate the pharmacokinetics and safety of oral BILR 355 administration alone and after coadministration with ritonavir (RTV) at 100 mg. Following a single dose of BILR 355 in oral solution, the mean half life (t1/2) was 2 to 4 h, with peak concentrations occurring at 0.5 to 1 h postadministration. The mean apparent clearance (CL/F) ranged from 79.2 to 246 liters/h for administered doses of 12.5 mg to 100 mg. This observed nonlinearity in CL/F resulted from the increased bioavailability attributed to a saturated absorption and/or elimination process at higher doses. In contrast, after the coadministration of single doses of 5 mg to 87.5 mg of BILR 355 with RTV, the mean CL/F ranged from 5.88 to 8.47 liters/h. Over the dose range (5 to 87.5 mg) studied, systemic BILR 355 exposures were approximately proportional to the doses administered when they were coadministered with RTV. With RTV coadministration, the mean t1/2 increased to 10 to 16 h, and the mean time of the maximum concentration in plasma lengthened to 1.5 to 5 h. Compared to the values for BILR 355 given alone, the mean area under the concentration-time curve from time zero to infinity, the maximum concentration in plasma, and the t1/2 of BILR 355 achieved after coadministration with RTV increased 15- to 30-fold, 2- to 5-fold, and 3- to 5-fold, respectively. In both studies, BILR 355 appeared to be safe and well tolerated in healthy volunteers when the outcomes in the treated volunteers were compared with those in the placebo group. PMID:18824608

  20. A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers.

    PubMed

    Chilengi, Roma; Juma, Rashid; Abdallah, Ahmed M; Bashraheil, Mahfudh; Lodenyo, Hudson; Nyakundi, Priscilla; Anabwani, Evelyn; Salim, Amina; Mwambingu, Gabriel; Wenwa, Ednah; Jemutai, Julie; Kipkeu, Chemtai; Oyoo, George O; Muchohi, Simon N; Kokwaro, Gilbert; Niehues, Tim; Lang, Trudie; Nzila, Alexis

    2011-03-16

    Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C(max)) was 160-200 nM and after 6 hours, the effective concentration (C(eff)) was <150 nM. Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C(eff) of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

  1. Pharmacokinetic evaluation of pramipexole.

    PubMed

    Antonini, Angelo; Calandrella, Daniela

    2011-10-01

    Immediate-release (IR) pramipexole dihydrochloride is indicated for the treatment of signs and symptoms of idiopathic Parkinson's disease (PD). It is administered alone (without levodopa) or in combination with levodopa, during the entire progress of the disease, up to an advanced stage. Currently, it is also indicated for the treatment of moderate-to-severe primary restless legs syndrome (RLS). An extended-release (ER) formulation of pramipexole has been developed to allow a once-daily administration and to provide more stable dopaminergic stimulation in PD patients. This review summarizes the overall pharmacokinetic profile of pramipexole for both the IR and ER formulations. Also discussed are the clinically relevant determinants of pramipexole peripheral pharmacokinetics and the potential role of genetic and clinical determinants in drug efficacy. Pramipexole is a non-ergot agonist with selective affinity for dopamine receptors of the D2 subfamily, in particular D3. Pramipexole has a very low affinity for serotoninergic 5-HT2A and 5-HT2B receptors, as well as D1-type receptors. Furthermore, it does not carry the risk to induce valvular heart disease or pulmonary and retroperitoneal fibrosis, seen with long-term use of the ergot-derived dopamine agonists. The recent introduction of a once-daily formulation poses significant advantages for patients, reflected by relatively stable plasma levels. The most obvious benefit is convenience of use and better adherence to treatment schedule. Additional advantages could include the opportunity to provide more continuous drug delivery in a fashion that could help minimize dyskinesia risk, if the drug is used early in the disease course.

  2. A Randomized Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Trabodenoson in Healthy Adult Volunteers

    PubMed Central

    Laties, Alan; Rich, Cadmus C.; Stoltz, Randall; Humbert, Vernon; Brickman, Chaim; McVicar, William

    2016-01-01

    Abstract Purpose: To investigate the safety, tolerability, and pharmacokinetics of trabodenoson, a highly selective adenosine mimetic targeting the adenosine A1 receptor. Methods: In Part 1, 60 healthy adult volunteers were randomized to 14 days of twice-daily topical monocular application of placebo or trabodenoson (200, 400, 800, 1,600, 2,400, or 3,200 μg). In Part 2, 10 subjects were randomized to placebo or 8 escalating doses of bilateral trabodenoson (total daily doses: 1,800–6,400 μg). Results: The incidence of treatment-related adverse events in Part 1 was similar in the trabodenoson (27.8%) and placebo (25.0%) groups. Most were mild in intensity. The most common adverse events (AEs) for trabodenoson and placebo were headache (25.0% vs. 33%, respectively) and eye pain (11.1% vs. 4.2%, respectively). Ocular AEs were infrequent (16.7% and 17.9%, respectively), were self-limited, lasted <24 h, and were typically mild in intensity. The most common ocular AE was eye pain (9.5% and 3.6%, respectively), with a single observation of ocular hyperemia (200 μg trabodenoson). Trabodenoson was rapidly absorbed [median time to maximum concentration (tmax): ∼0.08 to 0.27 h] and eliminated (t½: 0.48–2.0 h), with no evidence of drug accumulation. Systemic exposure to topical trabodenoson was dose related but not dose proportional, with a plateau effect at doses ≥2,400 mg per eye. No clinically significant treatment-related systemic AEs were observed, and increasing systemic exposure had no effect on heart rate or blood pressure. Conclusions: Ocular doses of trabodenoson up to 3,200 μg per eye were safe and well tolerated in the eye and resulted in no detectable systemic effects in healthy adult volunteers. PMID:27046445

  3. Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab'.

    PubMed

    Macfarlane, David J; Smart, Richard C; Tsui, Wendy W; Gerometta, Michael; Eisenberg, Paul R; Scott, Andrew M

    2006-06-01

    (99m)Tc-DI-DD-3B6/22-80B3 (Thromboview, hereafter abbreviated to (99m)Tc-DI-80B3 Fab') is a humanised, radiolabelled monoclonal antibody Fab' fragment with high affinity and specificity for the D-dimer domain of cross-linked fibrin. The purpose of this study was to evaluate the safety, pharmacokinetics and dosimetry of four increasing doses of (99m)Tc-DI-80B3 Fab' in healthy volunteers. Thirty-two healthy volunteers (18-70 years; 16 male, 16 female) received a single intravenous injection of 0.5, 1.0, 2.0 or 4.0 mg of (99m)Tc-DI-80B3 Fab'. Safety outcomes (vital signs, electrocardiography, haematology, biochemistry, adverse events and development of human anti-human antibodies) were assessed up to 30 days post injection. Blood and urine samples were collected up to 48 h post injection. Gamma camera images were acquired at 0.5, 1, 2, 4, 6 and 24 h post injection. Dosimetry was performed using standard MIRD methodology. No adverse events considered to be drug related were observed. Human anti-human antibody was not detectable in any subject during the follow-up period. (99m)Tc-DI-80B3 Fab' had a rapid initial plasma clearance (t (1/2)alpha=1 h). The pharmacokinetic profile of the Fab' fragment was generally linear across the four dose cohorts. By 24 h, 30-35% of the administered radioactivity appeared in the urine. There was marked renal accumulation with time, but no specific uptake was identified within other normal tissues. The effective dose was 9 mSv/750 MBq. (99m)Tc-DI-80B3 Fab' is well tolerated, is rapidly cleared and exhibits clinically acceptable dosimetry-characteristics well suited to a potential thrombus imaging agent.

  4. Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A.

    PubMed

    Taylor, Claribel P; Tummala, Sanjeev; Molrine, Deborah; Davidson, Lisa; Farrell, Richard J; Lembo, Anthony; Hibberd, Patricia L; Lowy, Israel; Kelly, Ciaran P

    2008-06-25

    Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.

  5. Open-Label, Dose Escalation Phase I Study in Healthy Volunteers to Evaluate the Safety and Pharmacokinetics of a Human Monoclonal Antibody to Clostridium difficile Toxin A

    PubMed Central

    Taylor, Claribel P.; Tummala, Sanjeev; Molrine, Deborah; Davidson, Lisa; Farrell, Richard J.; Lembo, Anthony; Hibberd, Patricia L.; Lowy, Israel; Kelly, Ciaran P.

    2009-01-01

    Background Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. Methods Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. Results Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean Cmax ranged from 6.82 mcg/ml for the 0.3 mg/kg cohort to 511 mcg/ml for the 20mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. Conclusion Administration of CDA1 as a single intravenous infusion was safe and well tolerated. Cmax increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway. PMID:18502001

  6. Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats.

    PubMed

    Sengupta, Pinaki; Nandi, Utpal; Pal, Tapan Kumar

    2012-02-01

    Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.

  7. A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic

    PubMed Central

    Buda, Jeffrey J; Carroll, F I; Kosten, Thomas R; Swearingen, Dennis; Walters, Bradford B

    2015-01-01

    Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1–6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect. PMID:25628006

  8. Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers

    PubMed Central

    Wu, Kai; Xu, Jianfeng; Fong, Regan; Yao, Xiaozhou; Xu, Yanmei; Guiney, William; Gray, Frank; Lockhart, Andrew

    2016-01-01

    Abstract. Objective: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). Methods: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 – 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. Results: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. Conclusions: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2. PMID:27719741

  9. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension.

    PubMed

    Savale, Laurent; Magnier, Romain; Le Pavec, Jérôme; Jaïs, Xavier; Montani, David; O'Callaghan, Dermot S; Humbert, Marc; Dingemanse, Jasper; Simonneau, Gérald; Sitbon, Olivier

    2013-01-01

    Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short- and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics. All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and event-free status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients. Significant improvements from baseline were observed in NYHA FC, 6 MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n=9) had significantly larger haemodynamic improvement after mean ± SD 5 ± 2 months. Mean follow-up time was 43 ± 19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH. These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.

  10. Pharmacokinetics and safety of intravitreal caspofungin.

    PubMed

    Shen, Ying-Cheng; Liang, Chiao-Ying; Wang, Chun-Yuan; Lin, Keng-Hung; Hsu, Min-Yen; Yuen, Hon-Leung; Wei, Li-Chen

    2014-12-01

    Caspofungin exhibits potent antifungal activities against Candida and Aspergillus species. The elimination rate and retinal toxicity of caspofungin were determined in this study to assess its pharmacokinetics and safety in the treatment of fungal endophthalmitis. Intravitreal injections of 50 μg/0.1 ml of caspofungin were administered to rabbits. Levels of caspofungin in the vitreous and aqueous humors were determined using high-performance liquid chromatography (HPLC) at selected time intervals (10 min and 1, 2, 4, 8, 16, 24, and 48 h), and the half-lives were calculated. Eyes were intravitreally injected with caspofungin to obtain concentrations of 10 μg/ml, 50 μg/ml, 100 μg/ml, and 200 μg/ml. Electroretinograms were recorded 4 weeks after injections, and the injected eyes were examined histologically. The concentrations of intravitreal caspofungin at various time points exhibited an exponential decay with a half-life of 6.28 h. The mean vitreous concentration was 6.06 ± 1.76 μg/ml 1 h after intravitreal injection, and this declined to 0.47 ± 0.15 μg/ml at 24 h. The mean aqueous concentration showed undetectable levels at all time points. There were no statistical differences in scotopic a-wave and b-wave responses between control eyes and caspofungin-injected eyes. No focal necrosis or other abnormality in retinal histology was observed. Intravitreal caspofungin injection may be considered to be an alternative treatment for fungal endophthalmitis based on its antifungal activity, lower retinal toxicity, and lower elimination rate in the vitreous. More clinical data are needed to determine its potential role as primary therapy for fungal endophthalmitis.

  11. Evaluation of a 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3-Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers.

    PubMed

    Yue, Yong; Collaku, Agron; Liu, Dongzhou J

    2017-08-16

    Acetaminophen (paracetamol) is a first-line treatment for mild and moderate pain. A twice-daily sustained-release (SR) formulation may be more convenient for chronic users than standard immediate-release (IR) acetaminophen. This randomized, 3-way crossover study evaluated pharmacokinetics and safety of single-dose 1500- and 2000-mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 μg/mL (TC≥4μg/mL ). Key secondary outcomes were area under the plasma concentration-time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC0-t ), AUC from 0 to infinity (AUC0-inf ), and maximum plasma acetaminophen concentration (Cmax ). TC≥4μg/mL from 2000-mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas TC≥4μg/mL for 1500-mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000-mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC0-12 , AUC0-t , and AUC0-inf . The extent of acetaminophen absorption from 1500-mg SR was significantly lower than that from IR acetaminophen. The 2000-mg SR represents a potential candidate formulation for 12-hour dosing with acetaminophen. © 2017, The American College of Clinical Pharmacology.

  12. Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects.

    PubMed

    Bruderer, Shirin; Hurst, Noémie; Kaufmann, Priska; Dingemanse, Jasper

    2014-01-01

    The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. Dose levels of selexipag up to 1,600 μg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials. © 2014 S. Karger AG, Basel.

  13. Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers.

    PubMed

    Wu, F; Zhao, X L; Wei, M J; Wang, S M; Zhou, H; Guo, S J; Zhang, P

    2012-12-01

    The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers.In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings.The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34 ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51 h; AUC0-24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13 ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43±5.63 ng/ml and AUCss (0-24) at 263.30±51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication.The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated.

  14. Evaluation of the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin administered as sham, postexposure prophylaxis of tetanus.

    PubMed

    Forrat, R; Dumas, R; Seiberling, M; Merz, M; Lutsch, C; Lang, J

    1998-02-01

    In a monocentric, double-blind, randomized trial, we examined the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin (P-HTIG). As part of the purification process, P-HTIG has undergone a heat treatment step (10 h at 60 degrees C) and the removal of Merthiolate. Forty-eight adults with a history of tetanus vaccination were randomized into four groups (n = 12 per group) to receive one of two different batches of this P-HTIG simultaneously with either tetanus-diphtheria (Td) vaccine (sham, postexposure prophylaxis of tetanus) or placebo. Local reactions at the injection site were followed for the first 3 days after injection, and systemic reactions were followed during the entire study period, i.e., up to 42 days posttreatment. Blood samples for tetanus antibody titer determination (enzyme-linked immunosorbent assay method) were drawn prior to treatment on day 0 and on days 1, 2, 3, 7, 14, 21, 28, 35, and 42. A normalization of tetanus antibody titers (subtraction of the day 0 value for each subject at each time period) was performed to assess the additive effect of P-HTIG on tetanus antibody titers. The pharmacokinetic parameters were determined by both a compartmental analysis (modelization) and a noncompartmental analysis. No severe adverse reactions were reported. The rate of local reactions at the P-HTIG injection site was 27%. All local reactions were mild and resolved within 2 days. In contrast, local reactions at the vaccine injection site were seen in 79% of the subjects. The rate of systemic reactions was similar in the P-HTIG plus Td vaccine group (33%) and in the P-HTIG plus placebo group (21%), and all these reactions were mild. In the P-HTIG plus placebo group, tetanus antibody titers rose to a maximum of 0.313+/-2.49 IU/ml after 4.4 days; in the P-HTIG plus Td vaccine group, a maximum concentration of 15.2+/-2.42 IU/ml was reached 19 days postinjection. In both groups, 100% of the patients had seroprotective levels of

  15. Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

    PubMed

    Gelotte, Cathy K; Prior, Mary Jane; Pendley, Charles; Zimmerman, Brenda; Lavins, Bernard J

    2010-07-01

    Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.

  16. A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients.

    PubMed

    Davis, Gary L; Nelson, David R; Terrault, Norah; Pruett, Timothy L; Schiano, Thomas D; Fletcher, Courtney V; Sapan, Christine V; Riser, Laura N; Li, Yufeng; Whitley, Richard J; Gnann, John W

    2005-08-01

    Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients.

  17. Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients

    PubMed Central

    Robb, Adelaide S.; DelBello, Melissa; Huss, Michael; McNamara, Nora; Sarkis, Elias; Scheffer, Russell; Poulsen, Lis H.; Chen, Grace; Lemming, Ole Michael; Areberg, Johan; Auby, Philippe

    2017-01-01

    Abstract Objective: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. Methods: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14–20 days with patients in the higher dose cohorts uptitrated over 2–6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. Results: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration–time curve from time 0 to 24 hours, was 30%–40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. Conclusion: The results suggest that the dosages of vortioxetine evaluated (5–20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials. PMID:28333546

  18. Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

    PubMed

    Findling, Robert L; Robb, Adelaide S; DelBello, Melissa; Huss, Michael; McNamara, Nora; Sarkis, Elias; Scheffer, Russell; Poulsen, Lis H; Chen, Grace; Lemming, Ole Michael; Areberg, Johan; Auby, Philippe

    2017-08-01

    The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14-20 days with patients in the higher dose cohorts uptitrated over 2-6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration-time curve from time 0 to 24 hours, was 30%-40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. The results suggest that the dosages of vortioxetine evaluated (5-20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

  19. Safety, Pharmacokinetic, and Pharmacodynamic Evaluation After Single and Multiple Ascending Doses of a Novel Selective Androgen Receptor Modulator in Healthy Subjects.

    PubMed

    Bhattacharya, Indranil; Tarabar, Sanela; Liang, Yali; Pradhan, Vivek; Owens, Jane; Oemar, Barry

    2016-06-01

    Tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of single ascending doses (SADs) and multiple ascending doses (MADs) of PF-06260414, a novel selective androgen receptor modulator, were assessed after oral administration in healthy subjects. Range of SAD and MAD levels tested were 1 to 400 mg and 3 to 100 mg BID, respectively (n = 8 per cohort). In addition, a 60-mg once-daily (n = 8) cohort and a Japanese cohort receiving 30 mg BID (n = 7) also received PF-06260414. Plasma was collected to study PK properties and hypothalamic-pituitary-gonadal (HPG) axis hormones. Tolerability was evaluated from adverse events (AEs), physical examinations, vital signs, ECGs, and clinical laboratory results. PF-06260414 was well tolerated with no serious AEs. The most frequently reported AEs were increase in alanine aminotransferase and headache, which were reported by 7 and 3 subjects, respectively. PF-06260414 had fast absorption (median Tmax, approximately 1-2 hours), a mean t½ of approximately 6.9 to 12.8 hours, time-independent PK properties and dose proportionality. Cmax and AUCτ geometric means in Japanese subjects were 98.6% and 79.5% higher than in Western subjects, respectively, but had similar HPG axis modulation. Changes in HPG axis hormones monitored in SADs were similar to placebo. Maximum placebo-corrected modulations were observed for total testosterone and sex hormone-binding globulin in the MAD 100-mg BID regimen. This study was the first to compare a number of different factors of PF-06260414, including tolerability, PK and PD properties, and ethnic differences between Japanese and Western healthy subjects. PF-06260414 had favorable PK properties and found that sex hormone-binding globulin, total testosterone, and HDL were most sensitive to modulation. ClinicalTrials.gov identifier: NCT02070939. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  20. [Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

    PubMed

    Goullé, Jean-Perre; Guerbet, Michel

    2014-03-01

    Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

  1. A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

    PubMed

    Shimizu, Toshio; Fukuoka, Kazuya; Takeda, Masayuki; Iwasa, Tutomu; Yoshida, Takeshi; Horobin, Joanna; Keegan, Mitchell; Vaickus, Lou; Chavan, Ajit; Padval, Mahesh; Nakagawa, Kazuhiko

    2016-05-01

    VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

  2. Pharmacokinetics and Safety of Single-Dose Inhaled Loxapine in Children and Adolescents.

    PubMed

    Selim, Sally; Riesenberg, Robert; Cassella, James; Kunta, Jeevan; Hellriegel, Edward; Smith, Mark A; Vinks, Alexander A; Rabinovich-Guilatt, Laura

    2017-10-01

    This multisite open-label study sought to characterize the pharmacokinetics and safety of a single dose of inhaled loxapine in children and adolescents. Loxapine powder for oral inhalation was administered via a single-use handheld drug device to children and adolescents (aged 10-17 years) with any condition warranting chronic antipsychotic use. Patients were dosed according to body weight and cohort (<50 kg [n = 15], 2.5 or 5 mg; ≥50 kg [n = 15], 5 or 10 mg); the first 6 patients (cohort 1) enrolled in each weight group received the lower dose. Patients were enrolled in the higher-dose group (cohort 2) after an interim pharmacokinetic and safety analysis of data from cohort 1. Blood samples were collected for 48 hours after dosing to determine the pharmacokinetic profile of loxapine and its metabolites. Safety was assessed using adverse event (AE), laboratory value, physical/neurologic examination, vital sign, electrocardiogram, suicidality, and extrapyramidal symptom assessment. Thirty patients were enrolled and evaluable for pharmacokinetics. Loxapine plasma concentrations peaked by 2 to 5 minutes in most patients; systemic exposure increased with dose in both weight subgroups. Loxapine terminal elimination half-life was ∼13 to 17 hours. The most common AEs were sedation and dysgeusia. Sedation was severe in 1 patient in the <50-kg group (2.5-mg dose) and 1 patient in the ≥50-kg group (5-mg dose). No AEs indicative of bronchospasm or other serious AEs were reported. Inhaled loxapine was rapidly absorbed and generally well tolerated in pediatric patients; no new safety signals were observed. © 2017, The American College of Clinical Pharmacology.

  3. 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

  4. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects.

    PubMed

    Dvorchik, Barry H; Brazier, David; DeBruin, Michael F; Arbeit, Robert D

    2003-04-01

    The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight ( approximately 20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life ( approximately 9 h), volume of distribution ( approximately 0.1 liters/kg), systemic clearance ( approximately 8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h ( approximately 54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.

  5. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis

    PubMed Central

    2013-01-01

    Introduction The aim of this study was to evaluate the safety, pharmacokinetics, and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid arthritis (RA). Methods This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with moderate to severe RA (≥6/66 swollen and ≥8/68 tender joints). Subjects were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. Endpoints included incidence of adverse events (AEs) and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics. Results Forty subjects were randomized to investigational product; one subject discontinued due to worsening of RA (placebo). The study was not designed to assess efficacy. AEs were reported by 70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three serious AEs were reported in two subjects; there were no opportunistic infections. Brodalumab treatment resulted in inhibition of IL-17 receptor signaling and receptor occupancy on circulating leukocytes. No treatment effects were observed with individual measures of RA disease activity. On day 85 (week 13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects achieved ACR70. Conclusions Multiple dose administration of brodalumab was tolerated in subjects with active RA. There was no evidence of a clinical response to brodalumab in subjects with RA. Trial registration ClinicalTrials.gov, NCT00771030 PMID:24286136

  6. Single-Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment.

    PubMed

    Dudkowski, Caroline; Karim, Aziz; Zhao, Zhen; Alonso, Alberto B; Garg, Dyal; Preston, Richard A

    2017-07-27

    Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M-II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase 1 parallel-group study that examined the single-dose (day 1) and multiple-dose (days 4-8) - 40 mg - pharmacokinetics of AZL and M-II in 16 subjects with mild and moderate hepatic impairment by Child-Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M-II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M-II. Single and multiple doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with mild and moderate hepatic impairment. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  7. Rufinamide in children with refractory epilepsy: pharmacokinetics, efficacy, and safety.

    PubMed

    Dahlin, Maria G; Ohman, Inger

    2012-10-01

    We examined the influence of age and type of concomitant antiepileptic drugs (AEDs) on the pharmacokinetics of rufinamide (RUF) as well as its efficacy and safety in 51 children with refractory epilepsy. In a retrospective noninterventional survey, dose-to-concentration ratios of RUF and concomitant AEDs were calculated: the weight-normalized dose (mg/kg/d) divided by the steady-state trough plasma drug level, which was used as a measure of clearance. During treatment with RUF concomitantly with valproic acid (VPA) young children, aged 0 to 4.9 years, had a low clearance of RUF, which did not differ from older children. If not on VPA but on enzyme inducers, young children had a threefold higher clearance of RUF than the older ones. In young children not on VPA, those on enzyme inducers had 1.7-fold higher clearance than those on nonenzyme inducers. In children neither on VPA nor on enzyme inducers, RUF clearance was age-dependent with higher clearance in younger children. Adding RUF did not change the pharmacokinetics of concomitantly used AEDs. Seizure response after 2 to 3 months on RUF treatment was found in 12 of 51 children (23.5%), at mean plasma level of 36.9 ± 22.0 µmol/L. Adverse events were reported in 41% of the patients of which fatigue was most frequent (24%). Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  8. Pharmacokinetics, tissue distribution and safety of cinnarizine delivered in lipid emulsion.

    PubMed

    Shi, Shuai; Chen, Hao; Lin, Xia; Tang, Xing

    2010-01-04

    The aim of this study was to assess the potential of cinnarizine loaded in lipid emulsion to modify the pharmacokinetics, tissue distribution and safety of cinnarizine. The cinnarizine-loaded emulsion (CLE) which can remain stable over 18-month storage at 4+/-2 degrees C was prepared by high-pressure homogenization. Nicomp 380 particle sizing system and HPLC were used to evaluate CLE in vitro, while UPLC/MS/MS for pharmacokinetic and tissue distribution study. The pharmacokinetics and tissue distributions of CLE were assessed by comparing with the solution form after intravenous administration to rats at a dose of 2mg/kg. The CLE showed significant higher AUC and lower clearance and distribution volume than those of solution form. This helped cinnarizine to reach higher level in vessel, and circulate in the blood stream for a longer time resulting in better therapeutic effect. The tissue distribution exhibited significant lower uptake of CLE emulsion in lung and brain, indicating the advantage of CLE over the solution form in reducing drug precipitation in vivo and toxicity in CNS. Drug safety assessment studies including hemolysis test, intravenous stimulation and injection anaphylaxis revealed that the CLE was safe for intravenous injection.

  9. Development of nano alpha-ketoglutarate nebulization formulation and its pharmacokinetic and safety evaluation in healthy human volunteers for cyanide poisoning.

    PubMed

    Sultana, Shaheen; Singh, Thakuri; Ahmad, Farhan Jalees; Bhatnagar, Aseem; Mittal, Gaurav

    2011-05-01

    Development of nano alpha-ketoglutarate (A-KG) nebulization formulation for neutralization of inhaled cyanide ion toxicity. Objectives of the present study were to (a) develop a novel A-KG nebulization formulation against cyanide poisoning, particularly hydrogen cyanide gas (b) validate its respiratory fraction in vitro and in vivo, and (c) create its pharmacokinetic data in human volunteers. The formulation was optimized on the basis of particle size of aerosolized droplets after nebulization in 6 volunteers. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized A-KG after radiolabeling it with Technetium-99m. The formulation was optimized using 30% ethanol-saline with particle size in the range of 300-500 nm. In vitro and in vivo studies showed that drug nebulization resulted in a significant respirable fraction of 65 ± 0.6% with whole lung deposition of 13 ± 1%. Human pharmacokinetic data was derived in 6 healthy human volunteers with peak serum concentration (C(max)) of 39 ± 3 μg/ml, while the area under curve (AUC) after inhalation was 376 ± 23 μg × h/ml indicating that the drug was rapidly and completely absorbed when targeted directly to lungs. Significant lung deposition of A-KG was achieved with the developed formulation. The formulation appears to have several advantages, including the potential of neutralizing inhaled CN(-) ions in the lungs themselves. It is a safe and efficacious procedure, suitable for hospital or ambulance use in accidental cyanide poisoning cases, or as a preventive approach for fire-rescue teams. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

    PubMed

    Salerno, Sara; Hornik, Christoph P; Cohen-Wolkowiez, Michael; Smith, P Brian; Ku, Lawrence C; Kelly, Matthew S; Clark, Reese; Gonzalez, Daniel

    2017-09-01

    Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to τ (AUCss,0-τ) and steady state maximal drug concentration (Cmaxss). Next, we used multivariable logistic regression to evaluate the association between simulated AUCss,0-τ and Cmaxss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUCss,0-τ and Cmaxss were reported. We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26-33) and postnatal age of 11 days (6-25). The median (interquartile range) piperacillin dose was 225 mg/kg/d (176-300). No significant associations were found between simulated piperacillin exposure (AUCss,0-τ and Cmaxss) and clinical and laboratory AEs. We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.

  11. Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.

    PubMed

    Chow, A T; Fowler, C; Williams, R R; Morgan, N; Kaminski, S; Natarajan, J

    2001-07-01

    The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

  12. Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis

    PubMed Central

    Cuffari, Carmen; Pierce, David; Korczowski, Bartosz; Fyderek, Krzysztof; Van Heusen, Heather; Hossack, Stuart; Wan, Hong; Edwards, Alena YZ; Martin, Patrick

    2016-01-01

    Background Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC). Aim To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC. Methods Participants (5–17 years of age; 18–82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model. Results Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%–45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified. Conclusion Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844. PMID:26893546

  13. The Safety, Pharmacokinetics, and Efficacy of Intraocular Celecoxib

    PubMed Central

    Kim, Stephen J.; Toma, Hassanain; Shah, Rohan; Kompella, Uday B.; Vooturi, Sunil K.; Sheng, Jinsong

    2014-01-01

    Purpose. To determine safety, pharmacokinetics, and anti-inflammatory effects of intraocular celecoxib. Methods. The right eye of animals was injected with 1.5, 3, or 6 mg celecoxib prepared in dimethyl sulfoxide (DMSO). Left eyes served as controls and received 0.1 mL DMSO. Electroretinograms (ERG) were obtained at baseline and at 1, 4, and 12 weeks, and eyes were enucleated afterward for histopathologic analysis. For pharmacokinetics, 3 mg celecoxib was injected, and vitreous and retina/choroid drug levels were then analyzed at specific time points. For efficacy, 1 μg lipopolysaccharide was injected to induce inflammation; the right eye was then injected with 3 mg celecoxib (six eyes) or 2 mg triamcinolone acetonide (six eyes) and the left eye with saline. Twenty-four hours later, aqueous fluid was removed, and total leukocyte concentration and prostaglandin E2 (PGE2) concentration were determined. Results. Histologic and ERG studies demonstrated no signs of retinal or optic nerve toxicity. After a single 3-mg injection, vitreous (0.06 μg/mL) and retina/choroid (132.31 μg/g) celecoxib concentrations at 8 weeks exceeded median inhibitory concentration. Treatment with celecoxib and triamcinolone significantly reduced total leukocyte count by 40% (P = 0.02) and 31% (P = 0.01), respectively. Reduction in PGE2 levels paralleled reduction in leukocyte counts (P < 0.05). There was no increase in intraocular pressure, but cataract formation was observed at higher concentrations. Conclusions. Intraocular injection of celecoxib appeared to be nontoxic and demonstrated excellent penetration into the retina/choroid and sustained drug levels out to 8 weeks. Celecoxib demonstrated potent anti-inflammatory effects, but there was an association with cataract formation at higher doses. PMID:24458149

  14. Phase 2, Randomized, Double-Blind, Dose-Ranging Study Evaluating the Safety, Tolerability, Population Pharmacokinetics, and Efficacy of Oral Torezolid Phosphate in Patients with Complicated Skin and Skin Structure Infections▿ † ‡

    PubMed Central

    Prokocimer, P.; Bien, P.; Surber, J.; Mehra, P.; DeAnda, C.; Bulitta, J. B.; Corey, G. R.

    2011-01-01

    Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections. S. aureus, the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials. PMID:21115795

  15. Pharmacokinetics and safety of tanaproget, a nonsteroidal progesterone receptor agonist, in healthy women.

    PubMed

    Bapst, Jody L; Ermer, James C; Ferron, Geraldine M; Foss, Deborah; Orczyk, Gayle P

    2006-11-01

    This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of the nonsteroidal progesterone receptor agonist, tanaproget. A randomized, double-blind, placebo-controlled, sequential-group study of ascending single doses of tanaproget was conducted in healthy, 25- to 45-year-old women on cycle days 8 to 12. Eight subjects (six active, two placebo) per cohort received a dose of 0.1, 0.3, 1, 3, 7 (+/-high-fat meal) or 15 mg. The maximum concentration (C(max)) of tanaproget occurred approximately 2 to 3 h after administration. The elimination half-life (t(1/2)) ranged from 12 to 30 h, and the oral clearance was approximately 70 L/h. The pharmacokinetics of tanaproget was not noticeably altered with a high-fat meal. All doses of tanaproget decreased cervical mucus scores (using a modified Insler method), indicating poor production and poor quality of cervical mucus. The most frequent treatment-emergent adverse events were vaginal bleeding/spotting, abdominal cramping and vomiting; their incidence was not dose related and most events were mild. Tanaproget was safe and well tolerated, decreased cervical mucus scores and had a pharmacokinetic profile acceptable for use as a once-daily oral contraceptive.

  16. Evaluation of Pharmacokinetic Assumptions Using a 443 ...

    EPA Pesticide Factsheets

    With the increasing availability of high-throughput and in vitro data for untested chemicals, there is a need for pharmacokinetic (PK) models for in vitro to in vivo extrapolation (IVIVE). Though some PBPK models have been created for individual compounds using in vivo data, we are now able to rapidly parameterize generic PBPK models using in vitro data to allow IVIVE for chemicals tested for bioactivity via high-throughput screening. However, these new models are expected to have limited accuracy due to their simplicity and generalization of assumptions. We evaluated the assumptions and performance of a generic PBPK model (R package “httk”) parameterized by a library of in vitro PK data for 443 chemicals. We evaluate and calibrate Schmitt’s method by comparing the predicted volume of distribution (Vd) and tissue partition coefficients to in vivo measurements. The partition coefficients are initially over predicted, likely due to overestimation of partitioning into phospholipids in tissues and the lack of lipid partitioning in the in vitro measurements of the fraction unbound in plasma. Correcting for phospholipids and plasma binding improved the predictive ability (R2 to 0.52 for partition coefficients and 0.32 for Vd). We lacked enough data to evaluate the accuracy of changing the model structure to include tissue blood volumes and/or separate compartments for richly/poorly perfused tissues, therefore we evaluated the impact of these changes on model

  17. Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

    PubMed Central

    Gonzalez, Daniel; Delmore, Paula; Bloom, Barry T.; Cotten, C. Michael; Poindexter, Brenda B.; McGowan, Elisabeth; Shattuck, Karen; Bradford, Kathleen K.; Smith, P. Brian; Cohen-Wolkowiez, Michael; Morris, Maurine; Yin, Wanrong; Benjamin, Daniel K.

    2016-01-01

    Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.) PMID:26926644

  18. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis.

    PubMed

    Ogura, Takashi; Taniguchi, Hiroyuki; Azuma, Arata; Inoue, Yoshikazu; Kondoh, Yasuhiro; Hasegawa, Yoshinori; Bando, Masashi; Abe, Shinji; Mochizuki, Yoshiro; Chida, Kingo; Klüglich, Matthias; Fujimoto, Tsuyoshi; Okazaki, Kotaro; Tadayasu, Yusuke; Sakamoto, Wataru; Sugiyama, Yukihiko

    2015-05-01

    A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone.

  19. Evaluation of microdosing to assess pharmacokinetic linearity in rats using liquid chromatography-tandem mass spectrometry.

    PubMed

    Balani, Suresh K; Nagaraja, Nelamangala V; Qian, Mark G; Costa, Arnaldo O; Daniels, J Scott; Yang, Hua; Shimoga, Prakash R; Wu, Jing-Tao; Gan, Liang-Shang; Lee, Frank W; Miwa, Gerald T

    2006-03-01

    The microdosing strategy allows for early assessment of human pharmacokinetics of new chemical entities using more limited safety assessment requirements than those requisite for a conventional phase I program. The current choice for evaluating microdosing is accelerator mass spectrometry (AMS) due to its ultrasensitivity for detecting radiotracers. However, the AMS technique is still expensive to be used routinely and requires the preparation of radiolabeled compounds. This report describes a feasibility study with conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology for oral microdosing assessment in rats, a commonly used preclinical species. The nonlabeled drugs fluconazole and tolbutamide were studied because of their similar pharmacokinetics characteristics in rats and humans. We demonstrate that pharmacokinetics can be readily characterized by LC-MS/MS at a microdose of 1 microg/kg for these molecules in rats, and, hence, LC-MS/MS should be adequate in human microdosing studies. The studies also exhibit linearity in exposure between the microdose and >or=1000-fold higher doses in rats for these drugs, which are known to show a linear dose-exposure relationship in the clinic, further substantiating the potential utility of LC-MS/MS in defining pharmacokinetics from the microdose of drugs. These data should increase confidence in the use of LC-MS/MS in microdose pharmacokinetics studies of new chemical entities in humans. Application of this approach is also described for an investigational compound, MLNX, in which the pharmacokinetics in rats were determined to be nonlinear, suggesting that MLNX pharmacokinetics at microdoses in humans also might not reflect those at the therapeutic doses. These preclinical studies demonstrate the potential applicability of using traditional LC-MS/MS for microdose pharmacokinetic assessment in humans.

  20. Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males.

    PubMed

    Shen, Zancong; Rowlings, Colin; Kerr, Brad; Hingorani, Vijay; Manhard, Kimberly; Quart, Barry; Yeh, Li-Tain; Storgard, Chris

    2015-01-01

    Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.

  1. Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males

    PubMed Central

    Shen, Zancong; Rowlings, Colin; Kerr, Brad; Hingorani, Vijay; Manhard, Kimberly; Quart, Barry; Yeh, Li-Tain; Storgard, Chris

    2015-01-01

    Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration–time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated. PMID:26170627

  2. Evaluation of Potential Pharmacokinetic Drug-Drug Interaction between Armodafinil and Aripiprazole in Healthy Adults.

    PubMed

    Darwish, M; Bond, M; Yang, R; Hellriegel, E T; Robertson, P

    2015-07-01

    Armodafinil, a moderate inducer of cytochrome P450 (CYP) 3A4, has been studied as adjunctive therapy to maintenance medications for major depressive episodes associated with bipolar I disorder. We evaluated the effect of daily dosing with armodafinil on the pharmacokinetics and safety of the CYP3A4 substrate aripiprazole, an atypical antipsychotic used to treat bipolar I disorder. Healthy adults received 15 mg aripiprazole alone and after armodafinil (250 mg/day) pretreatment. Pharmacokinetic parameters were derived from plasma concentrations of aripiprazole and its active metabolite, dehydro-aripiprazole, obtained over 16 days after each aripiprazole administration. Steady-state pharmacokinetics of armodafinil and its 2 circulating metabolites was assessed. Of 36 subjects enrolled, 24 were evaluable for pharmacokinetic analysis. Armodafinil reduced systemic exposure to aripiprazole (Cmax, - 8%; AUC0-∞, -34%) and dehydro-aripiprazole, which is both formed and eliminated in part via CYP3A4 (Cmax, - 10%; AUC0-∞, - 32%). Adverse events were generally consistent with known safety profiles of each agent. Systemic exposure to aripiprazole and dehydro-aripiprazole was moderately reduced following armodafinil pretreatment. The combination was generally well tolerated under the conditions studied. © Georg Thieme Verlag KG Stuttgart · New York.

  3. Pharmacokinetics and Safety of Famciclovir in Children with Herpes Simplex or Varicella-Zoster Virus Infection▿

    PubMed Central

    Sáez-Llorens, X.; Yogev, R.; Arguedas, A.; Rodriguez, A.; Spigarelli, M. G.; De León Castrejón, T.; Bomgaars, L.; Roberts, M.; Abrams, B.; Zhou, W.; Looby, M.; Kaiser, G.; Hamed, K.

    2009-01-01

    Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (∼12.5 mg/kg of body weight [BW] for children weighing <40 kg and 500 mg for children weighing ≥40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to <6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW0.696. An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose. PMID:19273678

  4. A novel paclitaxel microemulsion containing a reduced amount of Cremophor EL: pharmacokinetics, biodistribution, and in vivo antitumor efficacy and safety.

    PubMed

    Wang, Ying; Wu, Ke-Chun; Zhao, Bing-Xiang; Zhao, Xin; Wang, Xin; Chen, Su; Nie, Shu-Fang; Pan, Wei-San; Zhang, Xuan; Zhang, Qiang

    2011-01-01

    The purpose of this study was to prepare a novel paclitaxel (PTX) microemulsion containing a reduced amount of Cremophor EL (CrEL) which had similar pharmacokinetics and antitumor efficacy as the commercially available PTX injection, but a significantly reduced allergic effect due to the CrEL. The pharmacokinetics, biodistribution, in vivo antitumor activity and safety of PTX microemulsion was evaluated. The results of pharmacokinetic and distribution properties of PTX in the microemulsion were similar to those of the PTX injection. The antitumor efficacy of the PTX microemulsion in OVCRA-3 and A 549 tumor-bearing animals was similar to that of PTX injection. The PTX microemulsion did not cause haemolysis, erythrocyte agglutination or simulative reaction. The incidence and degree of allergic reactions exhibited by the PTX microemulsion group, with or without premedication, were significantly lower than those in the PTX injection group (P < .01). In conclusion, the PTX microemulsion had similar pharmacokinetics and anti-tumor efficacy to the PTX injection, but a significantly reduced allergic effect due to CrEL, indicating that the PTX microemulsion overcomes the disadvantages of the conventional PTX injection and is one way of avoiding the limitations of current injection product while providing suitable therapeutic efficacy.

  5. Safety and Pharmacokinetics of the Oral Iron Chelator SP-420 in β-thalassemia.

    PubMed

    Taher, Ali T; Saliba, Antoine N; Kuo, Kevin H; Giardina, Patricia J; Cohen, Alan R; Neufeld, Ellis J; Aydinok, Yesim; Kwiatkowski, Janet L; Jeglinski, Brenda I; Pietropaolo, Keith; Berk, Gregory; Viprakasit, Vip

    2017-09-22

    Our Phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n=3), 3 (n=3), 6 (n=3), 12 (n=3), and 24 (n=6) mg/kg or as a twice-daily dose of 9 mg/kg (n=6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for Cmax and AUC0-τ over the dose range evaluated. The median tmax ranged from 0.5 - 2.25 h and was not dose-dependent. The study was prematurely terminated by the sponsor due to renal adverse events including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal adverse events observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  6. Single-Dose Pharmacokinetics and Safety of Ziprasidone in Children and Adolescents

    ERIC Educational Resources Information Center

    Sallee, Floyd R.; Miceli, Jeffrey J.; Tensfeldt, Thomas; Robarge, Lisa; Wilner, Keith; Patel, Nick C.

    2006-01-01

    Objective: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. Method: A single-dose, open-label study of ziprasidone was conducted in youths…

  7. Single-Dose Pharmacokinetics and Safety of Ziprasidone in Children and Adolescents

    ERIC Educational Resources Information Center

    Sallee, Floyd R.; Miceli, Jeffrey J.; Tensfeldt, Thomas; Robarge, Lisa; Wilner, Keith; Patel, Nick C.

    2006-01-01

    Objective: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. Method: A single-dose, open-label study of ziprasidone was conducted in youths…

  8. Pharmacokinetics, efficacy, and safety of intravesical formulation of oxybutynin in patients with detrusor overactivity.

    PubMed

    Lehtoranta, Kari; Tainio, Hanna; Lukkari-Lax, Eeva; Hakonen, Tiina; Tammela, Teuvo L J

    2002-02-01

    To determine the pharmacokinetics of oxybutynin and its main active metabolite, N-desethyloxybutynin, after multiple dosage (5 mg/30 ml three times daily) of intravesical oxybutynin formulation. Furthermore, to determine the efficacy and safety of intravesical oxybutynin in the symptomatic relief of urge incontinence or urgency in adult patients with detrusor hyperreflexia or instability. Nine patients were randomly allocated to treatment with a special bladder instillation formulation of oxybutynin or placebo for two 14-day treatment periods in a double-blind, cross-over manner. The third, open study period was designed for pharmacokinetic purposes with all patients on the active drug. The pharmacokinetics was depicted by AUC0-24, Cmax, Cmin, and t(max), The efficacy was evaluated from the data collected from urinary voiding diaries and cystometries. The safety was measured by recording adverse events on questionnaires. Patients who were willing to continue with the intravesical oxybutynin treatment entered the 1-year extension part of the study. Oxybutynin was absorbed from the bladder with a geometric mean Cmax of 9.4 ng/ml and AUC0-24 of 92 ng x h/ml. For N-desethyloxybutynin, the geometric mean Cmax was 14.4 ng/ml and AUC0-24 186 ng x h/ml. Elimination of the drug was protracted, as there were detectable serum concentrations of both oxybutynin and N-desethyloxybutynin even 24 hours post-dose. The mean number of toilet visits/day decreased from the baseline value of 6.9 to 5.7 during oxybutynin treatment, whereas during the placebo period the value increased to 7.4 (p = 0.022). It remained at the same decreased level during the one-year follow-up period. Oxybutynin is readily absorbed from the bladder after intravesical administration. The serum concentrations of oxybutynin after single 5 mg intravesical doses are at least as high as those reported after oral drug intake, but the parent drug/metabolite ratio is much higher after intravesical administration. The

  9. Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects.

    PubMed

    Chen, Xia; Hu, Pei; Vaccaro, Nicole; Polidori, David; Curtin, Christopher R; Stieltjes, Hans; Sha, Sue; Weiner, Sveta; Devineni, Damayanthi

    2015-07-01

    Canagliflozin, an orally active sodium-glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0-∞, 10,521 ng · h/mL for 100 mg, 33,583 ng · h/mL for 300 mg; Cmax, 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t½ and the median Tmax of canagliflozin were independent of dose (t½, 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax, ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0-∞ were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. Pharmacokinetics (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in

  10. The efficacy, pharmacokinetics, and safety of a nevirapine to rilpivirine switch in virologically suppressed HIV-1-infected patients.

    PubMed

    Rokx, Casper; Blonk, Maren; Verbon, Annelies; Burger, David; Rijnders, Bart J A

    2015-01-01

    : This prospective, open-label nonrandomized controlled trial evaluated the efficacy, safety, and pharmacokinetics of substituting nevirapine/emtricitabine/tenofovir for rilpivirine/emtricitabine/tenofovir in 50 suppressed HIV-1 switchers. One hundred thirty-nine nonswitchers remained on nevirapine as controls. Week 12 HIV-1 RNA was <50 copies per milliliter in 92.0% of switchers and was <50 copies per milliliter at week 24 in 88.0% of switchers and 90.6% of nonswitchers (difference 2.6%, 95% confidence interval: -7.6% to 12.8%). Week 3 geometric mean nevirapine concentration was undetectable and week 1 geometric mean rilpivirine concentration (0.083 mg/L) was comparable with phase 3 trial (P = 0.747). Substituting nevirapine for rilpivirine resulted in ongoing virological suppression and did not have clinically relevant pharmacokinetic effects by cytochrome P450 interactions.

  11. Single-dose pharmacokinetics and safety of pegylated interferon-alpha2b in patients with chronic renal dysfunction.

    PubMed

    Gupta, Samir K; Pittenger, Amy L; Swan, Suzanne K; Marbury, Thomas C; Tobillo, Emlyn; Batra, Vijay; Sack, Marshall; Glue, Paul; Jacobs, Sheila; Affrime, Melton

    2002-10-01

    This study evaluates the pharmacokinetics and safety of pegylated interferon-alpha2b (PEG-Intron) following a single-dose subcutaneous injection into subjects with normal renal function, subjects with chronic renal impairment, and patients on hemodialysis. In this open-label, single-dose, parallel group study, subjects were divided into five groups according to their degree of renal function: four groups as defined by measured creatinine clearance and a fifth hemodialysis dependent group. They received 1 microg/kg PEG-Intron subcutaneously after a 10-hour fast. Pharmacokinetic and safety assessments were performed up to 168 hours postdose. Hemodialysis patients had a second PEG-Intron dose 12 hours prior to a hemodialysis session. PEG-Intron pharmacokinetic parameters (AUCtf, Cmax, and t1/2) increased progressively as CL(CR) declined. All subjects reported at least one adverse event, which were typical of those reported after alpha-interferon administration (e.g., flu-like symptoms, headache). Single-dose PEG-Intron administration to volunteers with normal renal function and chronic renal impairment was safe and well tolerated. In patients with CL(CR) < 30 ml/min, AUCand Cmax values were increased 90% compared with controls, while half-life was increased by up to 40% over controls. Based on the relationship between PEG-Intron apparent clearance and CL(CR), renal clearance accountsfor less than half of its total clearance. Hemodialysis did not affect PEG-Intron apparent clearance.

  12. Study to Evaluate the Effect of Rifampicin, Ketoconazole, and Omeprazole on the Pharmacokinetics of Sativex

    ClinicalTrials.gov

    2017-02-22

    Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Known Inducer of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Potent Inhibitor of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a CYP2C19 Inhibitor

  13. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects.

    PubMed

    Kersemaekers, Wendy M; van Iersel, Thijs; Nassander, Ulla; O'Mara, Edward; Waskin, Hetty; Caceres, Maria; van Iersel, Marlou L P S

    2015-02-01

    This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single- and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (n=45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC0-∞]) ranged from 4,890 to 46,400 ng · h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC0-∞ was 1.30 (1.19 to 1.41), indicating a greater-than-dose-proportional increase. The data for safety in part 1 show that 29/72 subjects had ≥1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous

  14. Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin: nonclinical safety and pharmacokinetics.

    PubMed

    Gaudreault, Jacques; Shiu, Vanessa; Bricarello, Ann; Christian, Brian J; Zuch, Christina L; Mounho, Barbara

    2005-01-01

    Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor approved for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic colorectal cancer. The Saltz regimen (irinotecan/5-FU/leucovorin [LV]) is a first-line treatment for this indication. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with the Saltz regimen to cynomolgus monkeys, and to determine if the pharmacokinetics of bevacizumab, irinotecan, SN38 (the active metabolite of irinotecan), or 5-FU were affected by combined administration. Male cynomolgus monkeys were intravenously administered the Saltz regimen (125 mg/m2 irinotecan, 500 mg/m2 5-FU, 20 mg/m2 LV) alone (n = 4) or concomitantly with 10 mg/kg bevacizumab (n = 5) on days 1 and 8. All animals survived to euthanasia on day 15. Adverse effects associated with the Saltz regimen included diarrhea and neutropenia. Macroscopically, two animals from each group had small thymus glands that correlated microscopically with lymphoid depletion. Myeloid hypoplasia and/or erythroid hyperplasia was observed in the sternal bone marrow of most animals. These effects were considered to be associated with the Saltz regimen; concomitant bevacizumab administration did not alter the severity of these findings. Irinotecan and 5-FU were observed to be rapidly eliminated (t1/2 = 1 h and 0.5 h, respectively). Although the number of animals in each group was small and no statistical comparison between groups was performed, bevacizumab did not affect the disposition of either agent. These results indicate that bevacizumab can be safely administered in combination with the Saltz regimen without pharmacokinetic interaction.

  15. Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants.

    PubMed

    Migoya, Elizabeth M; Mistry, Goutam C; Stone, Julie A; Comisar, Wendy; Sun, Peng; Norcross, Alisha; Bi, Sheng; Winchell, Gregory A; Ghosh, Kalyan; Uemera, Naoto; Deutsch, Paul J; Wagner, John A

    2011-02-01

    Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150- and 210-mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC(0-∞) after single 150- and 210-mg doses was 279.7 and 374.9 µg·h/mL, respectively; peak concentrations were 29.4 and 33.5 µg/mL, respectively; and 24-hour postdose concentrations were 2.8 and 4.2 µg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100-mg doses of caspofungin, day 21 geometric mean AUC(0-24) was 227.4 µg·h/mL, peak concentration was 20.9 µg/mL, and trough concentration was 4.7 µg/mL. Beta-phase t(1/2) was ~8 to ~13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.

  16. Safety and pharmacokinetics of a single 1500-mg dose of famciclovir in adolescents with recurrent herpes labialis.

    PubMed

    Block, Stan L; Yogev, Ram; Waldmeier, Felix; Hamed, Kamal

    2011-06-01

    An open-label study evaluated the safety (n = 53) and pharmacokinetics (n = 8) of single-dose therapy with 1500 mg famciclovir (prodrug of penciclovir) for recurrent herpes labialis in adolescents. Mean Cmax, mean AUC0-∞, and clearance for penciclovir were 9.37 μg/mL, 31.8 μg · h/mL, and 38.2 L/h, respectively, and within the range extrapolated from data in adults. Adverse events were generally mild and transient.

  17. 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

  18. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years.

    PubMed

    Nachman, Sharon; Zheng, Nan; Acosta, Edward P; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Wenning, Larissa; Spector, Stephen A; Frenkel, Lisa M; Alvero, Carmelita; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew

    2014-02-01

    IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥ 3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥ 1 log10 reduction between baseline and week 24. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%). Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥ 25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. NCT00485264.

  19. Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial.

    PubMed

    Ahmed, Amir I A; van den Elsen, Geke A H; Colbers, Angela; van der Marck, Marjolein A; Burger, David M; Feuth, Ton B; Rikkert, Marcel G M Olde; Kramers, Cornelis

    2014-09-01

    There is a great concern about the safety of THC-based drugs in older people (≥65 years), as most of THC-trials did not include such group. In this phase 1, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial, we evaluated the safety and pharmacokinetics of three oral doses of Namisol(®), a novel THC in tablet form, in older subjects. Twelve healthy older subjects (6 male; mean age 72±5 years) randomly received a single oral dose of 3mg, 5mg, or 6.5mg of THC or matching placebo, in a crossover manner, on each intervention day. The data for 11 subjects were included in the analysis. The data of 1 subject were excluded due to non-compliance to study medication. THC was safe and well tolerated. The most frequently reported adverse events (AEs) were drowsiness (27%) and dry mouth (11%). Subjects reported more AEs with THC 6.5mg than with 3mg (p=0.048), 5mg (p=0.034) and placebo (p=0.013). There was a wide inter-individual variability in plasma concentrations of THC. Subjects for whom the Cmax fell within the sampling period (over 2h), Cmax was 1.42-4.57ng/mL and Tmax was 67-92min. The AUC0-2h (n=11) was 1.67-3.51ng/mL. Overall, the pharmacodynamic effects of THC were smaller than effects previously reported in young adults. In conclusion, THC appeared to be safe and well tolerated by healthy older individuals. Data on safety and effectiveness of THC in frail older persons are urgently required, as this population could benefit from the therapeutic applications of THC.

  20. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects.

    PubMed

    Guzzo, Cynthia A; Furtek, Christine I; Porras, Arturo G; Chen, Cong; Tipping, Robert; Clineschmidt, Coleen M; Sciberras, David G; Hsieh, John Y K; Lasseter, Kenneth C

    2002-10-01

    Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.

  1. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects.

    PubMed

    Bozik, Michael E; Mather, James L; Kramer, William G; Gribkoff, Valentin K; Ingersoll, Evan W

    2011-08-01

    Dexpramipexole (KNS-760704; [6R]-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) is a novel synthetic amino-benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single-dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half-life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%-90% of dose). Food had no effect on the single-dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.

  2. Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects.

    PubMed

    Harrell, Robert E; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

    2016-05-01

    Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).

  3. Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and risperidone in healthy adults.

    PubMed

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2015-11-01

    Patients with bipolar I disorder and schizophrenia have an increased risk of obstructive sleep apnea. The effects of armodafinil, a weak cytochrome P450 (CYP) 3A4 inducer, on pharmacokinetics and safety of risperidone, an atypical antipsychotic used to treat major psychiatric illness, were investigated. Healthy subjects received 2 mg risperidone alone and after armodafinil pretreatment (titrated to 250 mg/day). Pharmacokinetic parameters were derived from plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (formed via CYP2D6 and CYP3A4), collected before and over 4 days after risperidone administration, and from steady-state plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone. Safety and tolerability were assessed. Thirty-six subjects receiving study drug were evaluable for safety; 34 were evaluable for pharmacokinetics. Risperidone maximum plasma concentration (C max) decreased from mean 16.5 ng/mL when given alone to 9.2 ng/mL after armodafinil pretreatment (geometric mean ratio [90 % CI] 0.55 [0.50-0.61]); area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) decreased from 92.3 to 44.5 ng·h/mL (geometric mean ratio [90 % CI] 0.51 [0.46-0.55]). C max and AUC0-∞ for 9-hydroxyrisperidone were also reduced (geometric mean ratios [90 % CI] 0.81 [0.77-0.85] and 0.73 [0.69-0.77], respectively). Adverse events were consistent with known safety profiles. Consistent with CYP3A4 induction, risperidone and 9-hydroxyrisperidone systemic exposure was reduced in the presence of armodafinil. Concomitant armodafinil and risperidone use may necessitate risperidone dosage adjustment, particularly when starting or stopping coadministration of the two drugs. However, any such decision should be based on patient disease state and clinical status.

  4. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy.

    PubMed

    Gabrielsson, Linda; Mattsson, Sofia; Fowler, Christopher J

    2016-10-01

    Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta-analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head-to-head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head-to-head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments.

  5. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy

    PubMed Central

    Gabrielsson, Linda; Mattsson, Sofia

    2016-01-01

    Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta‐analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head‐to‐head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head‐to‐head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments. PMID:27220803

  6. Pharmacokinetics, Safety, and Tolerability of Metformin in Healthy Elderly Subjects.

    PubMed

    Jang, Kyungho; Chung, Hyewon; Yoon, Jang-Soo; Moon, Seol-Joo; Yoon, Seo Hyun; Yu, Kyung-Sang; Kim, Kwangil; Chung, Jae-Yong

    2016-09-01

    Age-related physiological changes are known to alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Metformin is commonly used as first-line medication for management of diabetes in elderly patients. However, the PK and PD of metformin have not been sufficiently studied in elderly subjects. Here, 12 elderly subjects, aged 65 to 85 years, and 20 younger healthy volunteers were orally administered 750 mg of metformin 2 hours after dinner, followed by administration of a second dose (500 mg) 12 hours later. An oral glucose tolerance test (OGTT) was performed 2 hours after the second dose, with 75 g of glucose administered. Blood samples were collected at specific time points after the second metformin dose for the assessment of PK and the glucose-lowering effect of metformin. Elderly subjects exhibited 1.7 and 2.0 times higher average Cmax and AUC∞ than the younger subjects, respectively (P = .007 and .001, respectively), and t1/2 was comparable between the elderly and younger subjects. However, relative glucose level changes from baseline after metformin administration tended to be lower in elderly subjects. Systemic exposure to metformin was elevated by 50% or more in elderly subjects, whereas the glucose-lowering effect was similar compared to younger subjects after 2 doses of metformin. © 2016, The American College of Clinical Pharmacology.

  7. Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients

    PubMed Central

    Trachtman, Howard; Frymoyer, Adam; Lewandowski, Andrew; Greenbaum, Larry A.; Feig, Daniel I.; Gipson, Debbie S.; Warady, Bradley A.; Goebel, Jens W.; Schwartz, George J.; Lewis, Kenneth; Anand, Ravinder; Patel, Uptal D.

    2015-01-01

    Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options—including angiotensin-converting enzyme inhibitors—are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7–17 years) with stable kidney transplant function. Standard non-compartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n=13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30–59 ml/min per 1.73m2), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations. PMID:25807932

  8. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers.

    PubMed

    Gota, Vikram S; Maru, Girish B; Soni, Tejal G; Gandhi, Tejal R; Kochar, Nitin; Agarwal, Manish G

    2010-02-24

    Curcumin is the lipid-soluble antioxidant compound obtained from the rhizome of Curcuma longa Linn, also known as turmeric. Curcumin targets multiple chemotherapeutic and inflammatory pathways and has demonstrated safety and tolerability in humans, supporting its potential as a therapeutic agent; however, the clinical literature lacks conclusive evidence supporting its use as a therapeutic agent due to its low bioavailability in humans. The purpose of this study was to quantify plasma levels of free curcumin after dosing of a solid lipid curcumin particle (SLCP) formulation versus unformulated curcumin in healthy volunteers and to determine its tolerability and dose-plasma concentration relationship in late-stage osteosarcoma patients. Doses of 2, 3, and 4 g of SLCP were evaluated in 11 patients with osteosarcoma. Plasma curcumin levels were measured using a validated high-performance liquid chromatography method. The limit of detection of the assay was 1 ng/mL of curcumin. In healthy subjects, the mean peak concentration of curcumin achieved from dosing 650 mg of SLCP was 22.43 ng/mL, whereas plasma curcumin from dosing an equal quantity of unformulated 95% curcuminoids extract was not detected. In both healthy individuals and osteosarcoma patients, high interindividual variability in pharmacokinetics and nonlinear dose dependency was observed, suggesting potentially complex absorption kinetics. Overall, good tolerability was noted in both healthy and osteosarcoma groups.

  9. Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.

    PubMed

    Mash, D C; Kovera, C A; Pablo, J; Tyndale, R F; Ervin, F D; Williams, I C; Singleton, E G; Mayor, M

    2000-09-01

    Ibogaine is an indole alkaloid found in the roots of Tabernanthe Iboga (Apocynaceae family), a rain forest shrub that is native to western Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and thirst, and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and opiates. Anecdotal reports attest that a single dose of ibogaine eliminates opiate withdrawal symptoms and reduces drug craving for extended periods of time. The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. The majority of ibogaine biotransformation proceeds via CYP2D6, including the O-demethylation of ibogaine to 12-hydroxyibogamine (noribogaine). Blood concentration-time effect profiles of ibogaine and noribogaine obtained for individual subjects after single oral dose administrations demonstrate complex pharmacokinetic profiles. Ibogaine has shown preliminary efficacy for opiate detoxification and for short-term stabilization of drug-dependent persons as they prepare to enter substance abuse treatment. We report here that ibogaine significantly decreased craving for cocaine and heroin during inpatient detoxification. Self-reports of depressive symptoms were also significantly lower after ibogaine treatment and at 30 days after program discharge. Because ibogaine is cleared rapidly from the blood, the beneficial aftereffects of the drug on craving and depressed mood may be related to the effects of noribogaine on the central nervous system.

  10. Piperaquine population pharmacokinetics and cardiac safety in Cambodia.

    PubMed

    Vanachayangkul, Pattaraporn; Lon, Chanthap; Spring, Michele; Sok, Sommethy; Ta-Aksorn, Winita; Kodchakorn, Chanikarn; Pann, Sut-Thang; Chann, Soklyda; Ittiverakul, Mali; Sriwichai, Sabaithip; Buathong, Nillawan; Kuntawunginn, Worachet; So, Mary; Youdaline, Theng; Milner, Erin; Wojnarski, Mariusz; Lanteri, Charlotte; Manning, Jessica; Prom, Satharath; Haigney, Mark; Cantilena, Louis; Saunders, David

    2017-02-13

    Despite rising resistance, dihydroartemisinin-piperaquine (DP) remains a first line therapy for uncomplicated malaria in many parts of Cambodia. While generally well-tolerated as a 3-day regimen, compressed 2-day regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine concentration on QT interval prolongation, we pooled data from 3 randomized clinical trials between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between 2-day (2DP) and 3-day (3DP) regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with 1(st) order absorption and elimination without covariates was the best fit of the data. The linear slope-intercept model in this largely male population predicted 0.05 ms QT prolongation per ng/ml of piperaquine (5 milliseconds per 100 ng/ml). Though plasma half-life was similar in both regimens, peak and total piperaquine exposure were higher in those treated with 2DP. Furthermore, the correlation between plasma piperaquine and QT interval prolongation was stronger in the 2DP population. Neither time since last meal nor baseline serum magnesium or potassium levels had additive effects on QT prolongation. As electrocardiographic monitoring is often non-existent in malaria endemic areas, 2DP regimens should be avoided, and 3DP carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3 hour fast before and after administration, and avoiding concomitant QT-prolonging medications.

  11. Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers

    PubMed Central

    Abel, Samantha; van der Ryst, Elna; Rosario, Maria C; Ridgway, Caroline E; Medhurst, Christine G; Taylor-Worth, Richard J; Muirhead, Gary J

    2008-01-01

    Aims To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. Methods Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. Results Maraviroc is rapidly absorbed following oral administration, and plasma Tmax is achieved within 0.5–4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3–1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10–12 l h−1 and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. Conclusions Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate. PMID:18333861

  12. Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults.

    PubMed

    Pavliv, Leo; Voss, Bryan; Rock, Amy

    2011-01-01

    The pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults were evaluated. Methods In this randomized, double-blind, placebo-controlled, single-dose, crossover study, 12 healthy subjects age 18-65 years were randomized to receive a single dose of either 800 mg i.v. ibuprofen (infused over five to seven minutes) concomitantly with an oral placebo or 800 mg oral ibuprofen with concomitant i.v. placebo (0.9% sodium chloride injection). After a six-day washout period, subjects received the treatment not previously received. Blood samples were taken 1 hour before each dose of study medication was administered and throughout the 12 hours thereafter. Plasma ibuprofen concentrations were determined using validated liquid chromatography-tandem mass spectrometry methods. The frequency and severity of treatment-emergent adverse effects were monitored throughout the study. The maximum plasma concentration (C(max)) of i.v. ibuprofen was approximately twice that of oral ibuprofen, and the (t(max)) of i.v. ibuprofen was 0.11 hour, compared with 1.5 hours for oral ibuprofen. However, the elimination half-life of i.v. and oral ibuprofen did not differ, both of which were approximately 2 hours. Oral ibuprofen was 100% bioavailable; therefore, the area under the concentration-time curve did not differ between i.v. and oral ibuprofen. In addition, i.v. ibuprofen infused over five to seven minutes did not differ in terms of safety or tolerability when compared with oral ibuprofen. I.V. ibuprofen, when administered over five to seven minutes in healthy subjects, achieved a higher C(max) and a more-rapid t(max) than did oral ibuprofen and was found to be safe and well tolerated.

  13. Pharmacokinetics, safety and tolerability of an oral suspension of fexofenadine for children with allergic rhinitis.

    PubMed

    Segall, Nathan; Grubbe, Robert E; Levy, Arden L; Maloney, Michael J; Nayak, Anjuli S; Kittner, Barbara; Quesada, Javier T

    2008-01-01

    Allergic rhinitis (AR) is a common chronic condition in children and may impact a child's quality of life. Increasing treatment compliance may improve quality of life. An oral suspension of fexofenadine hydrochloride (HCl) has been developed to ease administration to children and may, therefore, improve treatment compliance. The purpose of this study was to assess the pharmacokinetic behavior, safety, and tolerability of a single dose of fexofenadine HCl oral suspension administered to children aged 2-5 years with allergic rhinitis. Children (aged 2-5 years) with AR were recruited in a multicenter, open-label, single-dose study. Fexofenadine HCl (30 mg) was administered as a 6-mg/mL suspension (5 mL). Plasma samples were collected up to 24 hours postdose. Adverse events (AEs); electrocardiograms (ECGs); vital signs; and clinical laboratory tests for hematology, blood chemistry, and urinalysis were analyzed to evaluate safety and tolerability. Fifty subjects completed the study. Mean maximum plasma concentration of fexofenadine was 224 ng/mL, and mean area under the plasma concentration curve was 898 ng . hour/mL. Treatment-emergent AEs were mild in intensity and reported in a total of seven subjects. No trends or clinically meaningful changes in mean ECG, vital sign, or clinical laboratory test data occurred during the study. In children aged 2-5 years, the exposure after a 30-mg dose of fexofenadine HCl suspension was similar to the exposures previously seen after a 30- and 60-mg dose of fexofenadine HCl in children aged 6-11 years and in adults, respectively. The suspension was also well tolerated.

  14. 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 Central

    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.

    2011-01-01

    Background 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. Design and Methods 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. Results Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (Cmax) was reached within 60–90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t1/2) 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) PMID:21173101

  15. Pharmacokinetics and preliminary safety data of a single oral dose of bosentan, a dual endothelin receptor antagonist, in cats.

    PubMed

    Puza, N; Papich, M G; Reinero, C; Chang, C H; Yu, D-H; Sharp, C; DeClue, A

    2014-04-01

    The objective of this study was to evaluate the pharmacokinetic properties and adverse effect profile of single-dose oral bosentan, a dual endothelin receptor antagonist, in healthy cats. Pharmacokinetic parameters were determined following a single mean ± SD oral dose of 3.2 ± 0.6 mg/kg of bosentan in 6 adult cats. Blood was collected for quantification of bosentan via high-performance liquid chromatography with ultraviolet detection. Blood and urine were evaluated for CBC, plasma biochemical profile, and urinalysis, and repeat physical examinations were performed to evaluate for adverse effects. The mean terminal half-life of bosentan was 20.4 ± 17.2 h. The mean peak plasma concentration was 0.49 ± 0.24 g/mL, and the mean time to maximum plasma concentration was 6.8 ± 8.6 h. The area under the curve was 5.14 ± 3.81 h·μg/mL. Oral bosentan tablets were absorbed in cats, and no clinically important adverse events were noted. Further evaluation of repeat dosing, investigation into the in vivo efficacy of decreasing endothelin-1 concentrations in cats, as well as safety in conjunction with other medications is warranted.

  16. Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-based universal placebo gel.

    PubMed

    Nel, Annalene M; Smythe, Shanique C; Habibi, Sepideh; Kaptur, Paulina E; Romano, Joseph W

    2010-10-01

    Dapivirine, a nonnucleoside reverse transcriptase inhibitor, is in development as a microbicide for the protection of women against HIV infection. A randomized, double-blind, phase 1 trial was conducted in 36 healthy HIV-negative women to compare the pharmacokinetics of 2 dapivirine vaginal gel formulations (0.05% each) and their safety with the hydroxyethyl cellulose-based universal placebo gel. Gel was self-administered once daily for a total of 11 days. Blood and vaginal fluid samples were collected sequentially over 24 days for pharmacokinetic analysis. Safety was evaluated by pelvic examination, colposcopy, adverse events, and clinical laboratory assessments. Adverse event profiles were similar for the 3 gels. Most events were mild and not related to study gel. Headache and vaginal hemorrhage (any vaginal bleeding) were most common. Plasma concentrations of dapivirine did not exceed 1.1 ng/mL. Steady-state conditions were reached within approximately 10 days. Dapivirine concentrations in vaginal fluids were slightly higher for Gel 4789, but Cmax values on days 1 and 14 were not significantly different. Terminal half-life was 72-73 hours in plasma and 15-17 hours in vaginal fluids. Both formulations of dapivirine gel were safe and well tolerated. Dapivirine was delivered to the lower genital tract at concentrations at least 5 logs greater than in vitro inhibitory concentrations.

  17. LNG Safety Assessment Evaluation Methods

    SciTech Connect

    Muna, Alice Baca; LaFleur, Angela Christine

    2015-05-01

    Sandia National Laboratories evaluated published safety assessment methods across a variety of industries including Liquefied Natural Gas (LNG), hydrogen, land and marine transportation, as well as the US Department of Defense (DOD). All the methods were evaluated for their potential applicability for use in the LNG railroad application. After reviewing the documents included in this report, as well as others not included because of repetition, the Department of Energy (DOE) Hydrogen Safety Plan Checklist is most suitable to be adapted to the LNG railroad application. This report was developed to survey industries related to rail transportation for methodologies and tools that can be used by the FRA to review and evaluate safety assessments submitted by the railroad industry as a part of their implementation plans for liquefied or compressed natural gas storage ( on-board or tender) and engine fueling delivery systems. The main sections of this report provide an overview of various methods found during this survey. In most cases, the reference document is quoted directly. The final section provides discussion and a recommendation for the most appropriate methodology that will allow efficient and consistent evaluations to be made. The DOE Hydrogen Safety Plan Checklist was then revised to adapt it as a methodology for the Federal Railroad Administration’s use in evaluating safety plans submitted by the railroad industry.

  18. Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension

    PubMed Central

    Vachiery, Jean-Luc; Huez, Sandrine; Gillies, Hunter; Layton, Gary; Hayashi, Naoto; Gao, Xiang; Naeije, Robert

    2011-01-01

    AIMS To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily. METHODS Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS After an acute increase, plasma concentrations stabilized within the range reported previously for a 20 mg oral tablet. At 0.5 h, mean ± SD changes from baseline were −8.4 ± 11.7 mmHg (systolic pressure), −2.6 ± 7.3 mmHg (diastolic pressure) and −3.5 ± 10.4 beats min−1 (heart rate). There was no symptomatic hypotension. CONCLUSIONS Although further research is warranted, a 10 mg sildenafil intravenous bolus appears to provide similar exposure, tolerability and safety to the 20 mg tablet. PMID:21219411

  19. Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels

    PubMed Central

    Papini, Juliana Zampoli Boava; Pedrazzoli Júnior, José; Calafatti, Silvana Aparecida; de Araújo, Daniele Ribeiro

    2017-01-01

    We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n = 6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 μg·kg−1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils' diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0–480 and ASC0–∞) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the enhancement of TR and M1 concentrations and the decrease of pupil size (miosis). Thus, F2 was effective in altering pharmacokinetics and pharmacodynamics effects of TR. PMID:28819627

  20. [Comparison of the pharmacokinetics and safety of a paclitaxel injection NK and Taxol injection in breast cancer patients].

    PubMed

    Sagara, Yoshiaki; Rai, Yoshiaki; Sagara, Yoshiatsu; Matsuyama, Yoshito; Baba, Shinichi; Tamada, Shugo; Sagara, Yasuaki; Ando, Mitsutake

    2009-02-01

    A paclitaxel injection NK (NK) is a generic product containing the same amount of ingredient as a Taxol Injection. We examined the pharmacokinetics and safety of NK compared to the original product in breast cancer patients. As a result, the transition of plasma paclitaxel concentration and pharmacokinetic parameter in NK and the original drug were almost equal, which suggested that these products were bioequivalent. In adjuvant therapy, there was no significant difference in adverse events reported, and these products were approximately equally safe.

  1. Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

    PubMed

    Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

    2015-02-01

    Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.

  2. Fructus Ligustri Lucidi in Osteoporosis: A Review of its Pharmacology, Phytochemistry, Pharmacokinetics and Safety.

    PubMed

    Chen, Beibei; Wang, Lili; Li, Lin; Zhu, Ruyuan; Liu, Haixia; Liu, Chenyue; Ma, Rufeng; Jia, Qiangqiang; Zhao, Dandan; Niu, Jianzhao; Fu, Min; Gao, Sihua; Zhang, Dongwei

    2017-09-05

    Background: Fructus Ligustri Lucidi (FLL) has now attracted increasing attention as an alternative medicine in the prevention and treatment of osteoporosis. This study aimed to provide a general review of traditional interpretation of the actions of FLL in osteoporosis, main phytochemical constituents, pharmacokinetics, pharmacology in bone improving effect, and safety. Materials and Methods: Several databases, including PubMed, China National Knowledge Infrastructure, National Science and Technology Library, China Science and Technology Journal Database, and Web of Science were consulted to locate publications pertaining to FLL. The initial inquiry was conducted for the presence of the following keywords combinations in the abstracts: Fructus Ligustri Lucidi, osteoporosis, phytochemistry, pharmacokinetics, pharmacology, osteoblasts, osteoclasts, salidroside. About 150 research papers and reviews were consulted. Results: FLL is assumed to exhibit anti-osteoporotic effects by improving liver and kidney deficiencies and reducing lower back soreness in Traditional Chinese Medicine (TCM). The data from animal and cell experiments demonstrate that FLL is able to improve bone metabolism and bone quality in ovariectomized, growing, aged and diabetic rats through the regulation of PTH/FGF-23/1,25-(OH)₂D₃/CaSR, Nox4/ROS/NF-κB, and OPG/RANKL/cathepsin K signaling pathways. More than 100 individual compounds have been isolated from this plant. Oleanolic acid, ursolic acid, salidroside, and nuzhenide have been reported to exhibit the anti-osteoporosis effect. The pharmacokinetics data reveals that salidroside is one of the active constituents, and that tyrosol is hard to detect under physiological conditions. Acute and subacute toxicity studies show that FLL is well tolerated and presents no safety concerns. Conclusions: FLL provides a new option for the prevention and treatment of osteoporosis, which attracts rising interests in identifying potential anti

  3. Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus.

    PubMed

    Iijima, Hiroaki; Kifuji, Takayuki; Maruyama, Nobuko; Inagaki, Nobuya

    2015-08-01

    Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved worldwide for the treatment of patients with type 2 diabetes mellitus (T2DM). The present study evaluated pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with T2DM. Canagliflozin, at doses of 25, 100, 200, or 400 mg, was administered as a single dose and, after a washout of 1 day, in repeated doses for 14 consecutive days to 61 subjects in a randomized, double-blind, placebo-controlled study. Plasma concentrations of canagliflozin and urinary glucose excretion (UGE) were measured, and renal threshold for glucose excretion (RTG) was calculated. Safety was evaluated on the basis of adverse event (AE) reports, blood and urine laboratory parameters, and vital signs. Plasma canagliflozin maximum concentration and area under the concentration-time curve (AUC) values increased in a dose-dependent manner with the time to maximum concentration (t max) of 1.0 h and elimination half-life (t 1/2) of 10.22-13.26 h on Day 1. No significant changes in t max and t 1/2 were observed after multiple-dose administration. The linearity factors, as calculated from the ratios of AUC0-24h on Day 16 to AUC0-∞ on Day 1, were close to 1 in all canagliflozin groups. Canagliflozin increased UGE0-24h (80-110 g/day with canagliflozin ≥100 mg) and decreased RTG from the first day of treatment; these effects were sustained during the entire period of multiple administration. No significant AEs were noted. Urine volume was slightly increased on Day 1, but subsequent changes after repeated doses for 14 days were small. Urinary sodium tended to be higher in the early treatment period, whereas no particular change was observed in serum osmolality and hematocrit. Canagliflozin increased UGE, decreased RTG, and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM. Mitsubishi Tanabe Pharma Corporation. ClinicalTrials.gov#NCT00707954.

  4. Pharmacokinetic modeling as an approach to assessing the safety of residual formaldehyde in infant vaccines.

    PubMed

    Mitkus, Robert J; Hess, Maureen A; Schwartz, Sorell L

    2013-06-07

    Formaldehyde is a one-carbon, highly water-soluble aldehyde that is used in certain vaccines to inactivate viruses and to detoxify bacterial toxins. As part of the manufacturing process, some residual formaldehyde can remain behind in vaccines at levels less than or equal to 0.02%. Environmental and occupational exposure, principally by inhalation, is a continuing risk assessment focus for formaldehyde. However, exposure to formaldehyde via vaccine administration is qualitatively and quantitatively different from environmental or occupational settings and calls for a different perspective and approach to risk assessment. As part of a rigorous and ongoing process of evaluating the safety of biological products throughout their lifecycle at the FDA, we performed an assessment of formaldehyde in infant vaccines, in which estimates of the concentrations of formaldehyde in blood and total body water following exposure to formaldehyde-containing vaccines at a single medical visit were compared with endogenous background levels of formaldehyde in a model 2-month-old infant. Formaldehyde levels were estimated using a physiologically-based pharmacokinetic (PBPK) model of formaldehyde disposition following intramuscular (IM) injection. Model results indicated that following a single dose of 200 μg, formaldehyde is essentially completely removed from the site of injection within 30 min. Assuming metabolism at the site of injection only, peak concentrations of formaldehyde in blood/total body water were estimated to be 22 μg/L, which is equivalent to a body burden of 66 μg or <1% of the endogenous level of formaldehyde. Predicted levels in the lymphatics were even lower. Assuming no adverse effects from endogenous formaldehyde, which exists in blood and extravascular water at background concentrations of 0.1 mM, we conclude that residual, exogenously applied formaldehyde continues to be safe following incidental exposures from infant vaccines. Published by Elsevier Ltd.

  5. The pharmacokinetics and safety of desvenlafaxine in subjects with chronic renal impairment.

    PubMed

    Nichols, A I; Richards, L S; Behrle, J A; Posener, J A; McGrory, S B; Paul, J

    2011-01-01

    Desvenlafaxine (administered as desvenlafaxine succinate), the major active metabolite of venlafaxine, is a new serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). To assess the pharmacokinetics, safety, and tolerability of desvenlafaxine in healthy volunteers vs. those with renal impairment. A single, oral, 100 mg dose of desvenlafaxine was administered to healthy subjects (n = 8) and subjects with mild (n = 9), moderate (n = 9), or severe (n = 7) renal impairment (24-h creatinine clearance, ml/min: 50 - 80, 30 - 50, or < 30 ml/min, respectively) or end-stage renal disease (ESRD; on dialysis.

  6. Pharmacokinetics and safety of the sesame lignans, sesamin and episesamin, in healthy subjects.

    PubMed

    Tomimori, Namino; Tanaka, Yasuhiro; Kitagawa, Yoshinori; Fujii, Wataru; Sakakibara, Yutaka; Shibata, Hiroshi

    2013-11-01

    A single-blind, placebo-controlled, parallel-group and multiple oral dose study was conducted in 48 healthy subjects to investigate the pharmacokinetics and safety of multiple oral doses of sesame lignans (sesamin and episesamin). Subjects were randomly divided into two groups. Each subject was administered 50 mg of sesame lignans (sesamin/episesamin=1/1) or placebo once daily for 28 days. The pharmacokinetics of the sesame lignans were investigated using 10 of the 24 subjects in the sesame lignans group. No serious adverse events were observed in this study. Sesamin was absorbed with a peak plasma concentration at 5.0 h. The plasma concentration of the main metabolite, SC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 2.4 h. Episesamin was also absorbed with a peak plasma concentration at 5.0 h and decreased with a terminal half-life of 7.1 h. The plasma concentration of the main metabolite, EC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 3.4 h. The plasma concentrations of sesamin and episesamin reached a steady state by day 7. Sesame lignans were confirmed to be safe and tolerable in healthy subjects. The results of the pharmacokinetic study demonstrate that no accumulation was observed following multiple 50 mg doses of sesame lignans.

  7. Multiple-Dose Safety and Pharmacokinetics of Oral Garenoxacin in Healthy Subjects

    PubMed Central

    Gajjar, D. A.; Bello, A.; Ge, Z.; Christopher, L.; Grasela, D. M.

    2003-01-01

    Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1,200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple- and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1,200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (Cmax) at the 100- and 1,200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 μg/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUCτ) for garenoxacin in plasma at the 100- and 1,200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 μg · h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and Cmax were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1,200-mg doses. Median values for the time to achieve Cmax were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and

  8. Safety, Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

    PubMed Central

    Cao, Guo-ying; Zhang, Ying-yuan; Guo, Bei-ning; Yu, Ji-cheng; Wu, Xiao-jie; Chen, Yuan-cheng; Wu, Ju-Fang; Shi, Yao-guo

    2014-01-01

    Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (Cmax) values were 4.826 μg/ml, 7.152 μg/ml, and 11.029 μg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC0–72 h) were 17.05 μg · h/ml, 39.30 μg · h/ml, and 61.98 μg · h/ml. The mean elimination half-life (t1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC0–72 h and AUC0–∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.) PMID:25092690

  9. Galantamine pharmacokinetics, safety, and tolerability profiles are similar in healthy Caucasian and Japanese subjects.

    PubMed

    Zhao, Qinying; Brett, Martin; Van Osselaer, Nancy; Huang, Fenglei; Raoult, Alain; Van Peer, Achiel; Verhaeghe, Tom; Hust, Rita

    2002-09-01

    The aim of this study was to compare the pharmacokinetics of galantamine in healthy Japanese and Caucasian subjects and assess the safety and tolerability of galantamine in both ethnic groups. Parallel groups of healthy Japanese (n = 13; 6 males and 7 females)and Caucasian (n = 12; 6 males and 6 females) subjects matched for weight and age received single oral doses of galantamine 4 mg, or galantamine 8 mg, or placebo in a double-blind, three-way crossover trial according to a randomized dosing schedule. Concentrations of galantamine and norgalantamine were determined in plasma and urine samples taken up to 48 and 24 hours after dosing, respectively. Safety and tolerability were monitored throughout the trial by recording adverse events, laboratory tests, and cardiovascular parameters. The mean plasma concentration-time profiles of galantamine were very similar after single doses of galantamine (4 and 8 mg), and there was an approximate dose proportionality of galantamine pharmacokinetic parameters in both Caucasian and Japanese ethnic groups. The mean (+/- SD) pharmacokinetic parameters in the two ethnic groups did not show any clinically relevant differences. The ratios for the area under the plasma-concentration curve from time zero to infinity (AUC)0-infinity) in Japanese:Caucasian subjects with 4 and 8 mg doses were 103% (90% confidence interval [CII = 92-116) and 107% (90% CI = 94-121), respectively. Ratios for maximum plasma concentration (Cmax) values were 107% (90% CI= 90-127) and 108% (90% CI= 95-123), respectively. These ratios and associated 90% CIs were within the 80% to 125% range limit of bioequivalence. Analysis of variance (ANOVA) showed that these ratio values demonstrated no statistically significant difference between the two ethnic groups. There was no overt difference in the adverse event profile in Japanese subjects compared with Caucasian subjects. There were no serious adverse events, and no subjects discontinued from the study because of

  10. Safety and pharmacokinetics of the antiorthopoxvirus compound ST-246 following repeat oral dosing in healthy adult subjects.

    PubMed

    Jordan, Robert; Chinsangaram, Jarasvech; Bolken, Tove' C; Tyavanagimatt, Shanthakumar R; Tien, Deborah; Jones, Kevin F; Frimm, Annie; Corrado, Michael L; Pickens, Margaret; Landis, Patrick; Clarke, Jean; Marbury, Thomas C; Hruby, Dennis E

    2010-06-01

    ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies.

  11. Safety and Pharmacokinetics of the Antiorthopoxvirus Compound ST-246 following Repeat Oral Dosing in Healthy Adult Subjects▿

    PubMed Central

    Jordan, Robert; Chinsangaram, Jarasvech; Bolken, Tove' C.; Tyavanagimatt, Shanthakumar R.; Tien, Deborah; Jones, Kevin F.; Frimm, Annie; Corrado, Michael L.; Pickens, Margaret; Landis, Patrick; Clarke, Jean; Marbury, Thomas C.; Hruby, Dennis E.

    2010-01-01

    ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies. PMID:20385870

  12. Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
.

    PubMed

    Schultze-Mosgau, Marcus-Hillert; Schuett, Barbara; Hafner, Frank-Thorsten; Zollmann, Frank; Kaiser, Andreas; Hoechel, Joachim; Rohde, Beate

    2017-01-01

    Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
.

  13. A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of 2 and 4 Weeks of Twice-Daily Ocular Trabodenoson in Adults with Ocular Hypertension or Primary Open-Angle Glaucoma

    PubMed Central

    Sall, Kenneth N.; DuBiner, Harvey; Slomowitz, Natanya; McVicar, William; Rich, Cadmus C.; Baumgartner, Rudolf A.

    2016-01-01

    Abstract Purpose: To evaluate the safety and ocular hypotensive efficacy of 4 trabodenoson doses administered twice daily over 14 or 28 days in subjects with ocular hypertension or primary open-angle glaucoma (POAG). Methods: In this multicenter, randomized, double-masked, placebo-controlled, dose-escalation Phase 2 study, patients received unilateral topical twice-daily trabodenoson (50, 100, or 200 mcg) or placebo for 14 days, or 500 mcg trabodenoson or placebo for 28 days. Ocular and systemic safety and tolerability were assessed by examinations, clinical and laboratory studies. Intraocular pressure (IOP) was assessed using Goldmann tonometry. Results: Trabodenoson was well tolerated; no clinically meaningful ocular or systemic side effects were identified. Trabodenoson produced a dose-dependent IOP reduction. IOP reductions in the 500 mcg group were significantly greater than placebo at all time points at Day 28. Mean IOP reductions from diurnal baseline ranged from −3.5 to −5.0 mmHg with a mean change of −4.1 mmHg in the 500 mcg group compared −1.0 to −2.5 mmHg with a mean change of −1.6 mmHg for the placebo group, and the Day 28 drop was significantly greater than at Day 14 (P = 0.0163) indicating improvement in IOP lowering with longer treatment time. IOP remained significantly reduced 24 h after the final 500 mcg dose (P = 0.048). Conclusion: Twice-daily ocular doses of trabodenoson, from 50 to 500 mcg, were well tolerated and showed a dose-related decrease in IOP that was statistically significant and clinically relevant at 500 mcg in patients with ocular hypertension or POAG. PMID:27002298

  14. A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of 2 and 4 Weeks of Twice-Daily Ocular Trabodenoson in Adults with Ocular Hypertension or Primary Open-Angle Glaucoma.

    PubMed

    Myers, Jonathan S; Sall, Kenneth N; DuBiner, Harvey; Slomowitz, Natanya; McVicar, William; Rich, Cadmus C; Baumgartner, Rudolf A

    2016-10-01

    To evaluate the safety and ocular hypotensive efficacy of 4 trabodenoson doses administered twice daily over 14 or 28 days in subjects with ocular hypertension or primary open-angle glaucoma (POAG). In this multicenter, randomized, double-masked, placebo-controlled, dose-escalation Phase 2 study, patients received unilateral topical twice-daily trabodenoson (50, 100, or 200 mcg) or placebo for 14 days, or 500 mcg trabodenoson or placebo for 28 days. Ocular and systemic safety and tolerability were assessed by examinations, clinical and laboratory studies. Intraocular pressure (IOP) was assessed using Goldmann tonometry. Trabodenoson was well tolerated; no clinically meaningful ocular or systemic side effects were identified. Trabodenoson produced a dose-dependent IOP reduction. IOP reductions in the 500 mcg group were significantly greater than placebo at all time points at Day 28. Mean IOP reductions from diurnal baseline ranged from -3.5 to -5.0 mmHg with a mean change of -4.1 mmHg in the 500 mcg group compared -1.0 to -2.5 mmHg with a mean change of -1.6 mmHg for the placebo group, and the Day 28 drop was significantly greater than at Day 14 (P = 0.0163) indicating improvement in IOP lowering with longer treatment time. IOP remained significantly reduced 24 h after the final 500 mcg dose (P = 0.048). Twice-daily ocular doses of trabodenoson, from 50 to 500 mcg, were well tolerated and showed a dose-related decrease in IOP that was statistically significant and clinically relevant at 500 mcg in patients with ocular hypertension or POAG.

  15. Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents

    PubMed Central

    Gonzalez, Daniel; Palazzi, Debra L.; Bhattacharya-Mithal, Leena; Al-Uzri, Amira; James, Laura P.; Bradley, John; Neu, Natalie; Jasion, Theresa; Hornik, Christoph P.; Smith, P. Brian; Benjamin, Daniel K.; Keedy, Kara; Fernandes, Prabhavathi

    2016-01-01

    We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.) PMID:26883693

  16. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety.

    PubMed

    Badros, A Z; Vij, R; Martin, T; Zonder, J A; Kunkel, L; Wang, Z; Lee, S; Wong, A F; Niesvizky, R

    2013-08-01

    This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50-80 ml/min, 30-49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m(2) (Cycle 1), 20 mg/m(2) (Cycle 2) and 27 mg/m(2) (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m(2), proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.

  17. Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability

    PubMed Central

    Usach, Iris; Melis, Virginia; Peris, José-Esteban

    2013-01-01

    Introduction Human immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection. Discussion First-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186. Conclusions This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research. PMID:24008177

  18. Effect of food on the pharmacokinetics of TAS-102 and its efficacy and safety in patients with advanced solid tumors.

    PubMed

    Yoshino, Takayuki; Kojima, Takashi; Bando, Hideaki; Yamazaki, Tomoko; Naito, Yoichi; Mukai, Hirofumi; Fuse, Nozomu; Goto, Koichi; Ito, Yuko; Doi, Toshihiko; Ohtsu, Atsushi

    2016-05-01

    TAS-102, a novel oral antitumor agent, consists of trifluridine and tipiracil hydrochloride (molar ratio, 1:0.5). We investigated the effects of food on trifluridine and tipiracil hydrochloride. The efficacy and safety of TAS-102 were evaluated in patients with advanced solid tumors. We analyzed drug pharmacokinetics using a randomized, single-dose, two-treatment (fed versus fasting), two-period, two-sequence cross-over design, followed by repeated administration. Patients were given single doses of TAS-102 (35 mg/m(2) ) in the pharmacokinetic phase and received twice-daily doses of TAS-102 in 28-day cycles in the repeated administration phase for evaluating efficacy and safety. Food showed no effect on the area under the curve from 0 to 12 h or 0 h-infinity values of trifluridine following administration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%. Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively. During the repeated administration, stable disease was observed in nine patients with rectal, small-cell lung, breast, thymic, duodenal, and prostate cancers. Major adverse events were neutropenia, leukopenia, anemia, and nausea. Postprandial administration was optimal for TAS-102 because trifluridine's area under the curve was not changed by food, indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest that TAS-102 would be an effective treatment for small-cell lung, thymic, and colorectal cancers. This trial is registered with the Japan Pharmaceutical Information Center (no. JapicCTI-111482). © 2016 The Authors. Cancer Science published by John Wiley & Sons

  19. A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients.

    PubMed

    Kanai, Masashi; Otsuka, Yoshihiko; Otsuka, Kazunori; Sato, Maremi; Nishimura, Takafumi; Mori, Yukiko; Kawaguchi, Michiya; Hatano, Etsuro; Kodama, Yuzo; Matsumoto, Shigemi; Murakami, Yoshiki; Imaizumi, Atsushi; Chiba, Tsutomu; Nishihira, Jun; Shibata, Hiroyuki

    2013-06-01

    A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients. Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated. Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range, 47-1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179-1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin administration for >9 months. Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.

  20. Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration.

    PubMed

    Wang, Hong-yun; Chen, Xia; Jiang, Ji; Shi, Jun; Hu, Pei

    2016-02-01

    To evaluate the SimCYP simulator ethnicity-specific population model for predicting the pharmacokinetics of midazolam, a typical CYP3A4/5 substrate, in Chinese after oral administration. The physiologically based pharmacokinetic (PBPK) model for midazolam was developed using a SimCYP population-based simulator incorporating Chinese population demographic, physiological and enzyme data. A clinical trial was conducted in 40 Chinese subjects (the half was females) receiving a single oral dose of 15 mg midazolam. The subjects were separated into 4 groups based on age (20-50, 51-65, 66-75, and above 76 years), and the pharmacokinetics profiles of each age- and gender-group were determined, and the results were used to verify the PBPK model. Following oral administration, the simulated profiles of midazolam plasma concentrations over time in virtual Chinese were in good agreement with the observed profiles, as were AUC and Cmax. Moreover, for subjects of varying ages (20-80 years), the ratios of predicted to observed clearances were between 0.86 and 1.12. The SimCYP PBPK model accurately predicted the pharmacokinetics of midazolam in Chinese from youth to old age. This study may provide novel insight into the prediction of CYP3A4/5-mediated pharmacokinetics in the Chinese population relative to Caucasians and other ethnic groups, which can support the rational design of bridging clinical trials.

  1. Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration

    PubMed Central

    Wang, Hong-yun; Chen, Xia; Jiang, Ji; Shi, Jun; Hu, Pei

    2016-01-01

    Aim: To evaluate the SimCYP simulator ethnicity-specific population model for predicting the pharmacokinetics of midazolam, a typical CYP3A4/5 substrate, in Chinese after oral administration. Methods: The physiologically based pharmacokinetic (PBPK) model for midazolam was developed using a SimCYP population-based simulator incorporating Chinese population demographic, physiological and enzyme data. A clinical trial was conducted in 40 Chinese subjects (the half was females) receiving a single oral dose of 15 mg midazolam. The subjects were separated into 4 groups based on age (20–50, 51–65, 66–75, and above 76 years), and the pharmacokinetics profiles of each age- and gender-group were determined, and the results were used to verify the PBPK model. Results: Following oral administration, the simulated profiles of midazolam plasma concentrations over time in virtual Chinese were in good agreement with the observed profiles, as were AUC and Cmax. Moreover, for subjects of varying ages (20–80 years), the ratios of predicted to observed clearances were between 0.86 and 1.12. Conclusion: The SimCYP PBPK model accurately predicted the pharmacokinetics of midazolam in Chinese from youth to old age. This study may provide novel insight into the prediction of CYP3A4/5-mediated pharmacokinetics in the Chinese population relative to Caucasians and other ethnic groups, which can support the rational design of bridging clinical trials. PMID:26592516

  2. Dose comparison of conivaptan (Vaprisol®) in patients with euvolemic or hypervolemic hyponatremia – efficacy, safety, and pharmacokinetics

    PubMed Central

    Palmer, Biff F; Rock, Amy D; Woodward, Emily J

    2016-01-01

    Purpose This study aimed to evaluate the efficacy, safety, and pharmacokinetics of 20 and 40 mg/day conivaptan (Vaprisol®) in patients with hypervolemic or euvolemic hyponatremia. Methods Hyponatremic patients – serum sodium (sNa) ≤130 mEq/L – received either 20 or 40 mg/day of conivaptan for 4 days, following an initial 20 mg loading dose. Efficacy was evaluated by the magnitude and extent of change in sNa. Safety was evaluated by the incidence of adverse events, changes in vital signs and laboratory parameters, rate of sNa correction, and frequency of infusion-site reactions. Pharmacokinetic parameters were also measured. Results A total of 37 patients received 20 mg/day and 214 patients received 40 mg/day conivaptan. Baseline-adjusted sNa-area under the concentration–time curve increased by an average of 753.8±499.9 mEq·hr/L (20 mg/day) and 689.2±417.3 mEq·hr/L (40 mg/day) over the course of the 4-day treatment period. The majority of patients in both treatment groups achieved a 4 mEq/L increase in sNa over baseline in ~24 hours (82.5%). Average increase in sNa after 4 days was ~10 mEq/L, varying with dosage level and baseline volume status. Treatment success (normal sNa or increase of ≥6 mEq/L) was attained by 70.3% of patients in the 20 mg/day group and 72.0% in the 40 mg/day group. Conclusion Both 20 and 40 mg/day doses of conivaptan are efficacious in increasing sNa over 4 days of treatment with no observed increase in the frequency of adverse events or specific infusion-site reactions using the higher dose. The pharmacokinetic parameters of both doses were similar to what has been reported previously, exhibiting greater-than-dose-proportional plasma concentrations. PMID:26848258

  3. Pharmacokinetics and safety of olopatadine hydrochloride 0.77% in healthy subjects with asymptomatic eyes: data from 2 independent clinical studies.

    PubMed

    Meier, Edward; Narvekar, Abhijit; Iyer, Ganesh R; DuBiner, Harvey B; Vutikullird, Apinya; Wirta, David; Sall, Kenneth

    2017-01-01

    To assess the pharmacokinetics and safety of hydrochloride ophthalmic solution 0.77% olopatadine from 2 independent (Phase I and Phase III, respectively) clinical studies in healthy subjects. The Phase I, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥18 years old (N=36) to assess the systemic pharmacokinetics of olopatadine 0.77% following single- and multiple-dose exposures. The Phase III, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥2 years old (N=499) to evaluate long-term ocular safety of olopatadine 0.77%. Subjects received olopatadine 0.77% or vehicle once daily bilaterally for 7 days in the pharmacokinetic study and 6 weeks in the safety study. In the pharmacokinetic study, olopatadine 0.77% was absorbed slowly and reached a peak plasma concentration (Cmax) of 1.65 ng/mL following single-dose and 1.45 ng/mL following multiple-dose exposures in 2 hours (time to reach maximum plasma concentration [Tmax]). After reaching peak concentrations, olopatadine showed a similar mono-exponential decay following single and multiple doses with mean elimination half-life ranging from 2.90 to 3.40 hours. No accumulation in olopatadine exposure (Cmax and area under the plasma concentration-time curve from 0 to 12 hours) was evident after multiple doses when compared to single dose. In the safety study, treatment-emergent adverse events were reported in 26.7% and 31.4% of subjects with olopatadine 0.77% and vehicle, respectively. Blurred vision was the most frequent ocular treatment-emergent adverse event in both treatment groups (olopatadine 0.77% vs vehicle, 4.8% vs 4.1%). No deaths or serious adverse events were reported during the study. Olopatadine 0.77% had minimal systemic exposure or accumulation in healthy subjects and was well tolerated in both adult and pediatric subjects.

  4. Deferasirox pharmacokinetic evaluation in β-thalassaemia paediatric patients.

    PubMed

    Allegra, Sarah; Cusato, Jessica; De Francia, Silvia; Pirro, Elisa; Massano, Davide; Piga, Antonio; D'Avolio, Antonio

    2017-05-01

    Iron chelation in the transfusion-dependent anaemias management is essential to prevent end-organ damage and to improve survival. Deferasirox is a once-daily orally active tridentate selective iron chelator which pharmacokinetic disposition could influence treatment efficacy and toxicity. Therapeutic drug monitoring is an important tool for optimizing drug utilization and doses. A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from paediatric patients with β-thalassaemia. Samples obtained after 5 days of washout or in naïve patients before and after 2, 4, 6 and 24 h drug administration were evaluated. Associations between variables were tested using the Pearson test. Twenty paediatric patients were enrolled; they were mainly men (13.65%), with median age of 6.35 years and body mass index of 15.45 kg/m(2) . Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive, but not significant, correlation (r = 0.363; P = 0.115) was found between deferasirox area under the concentration curve over 24 h (AUC) and drug dose. Monitoring plasma deferasirox concentrations appears beneficial for guiding appropriate patient treatment, enhancing effectiveness and minimizing toxicity. © 2016 Royal Pharmaceutical Society.

  5. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease.

    PubMed

    Gill, Joan C; Castaman, Giancarlo; Windyga, Jerzy; Kouides, Peter; Ragni, Margaret; Leebeek, Frank W G; Obermann-Slupetzky, Ortrun; Chapman, Miranda; Fritsch, Sandor; Pavlova, Borislava G; Presch, Isabella; Ewenstein, Bruce

    2015-10-22

    This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227.

  6. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease

    PubMed Central

    Gill, Joan C.; Castaman, Giancarlo; Windyga, Jerzy; Kouides, Peter; Ragni, Margaret; Leebeek, Frank W. G.; Obermann-Slupetzky, Ortrun; Chapman, Miranda; Fritsch, Sandor; Pavlova, Borislava G.; Presch, Isabella

    2015-01-01

    This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII:C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII:C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII:C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227. PMID:26239086

  7. Safety climate and attitude as evaluation measures of organizational safety.

    PubMed

    Isla Díaz, R; Díaz Cabrera, D

    1997-09-01

    The main aim of this research is to develop a set of evaluation measures for safety attitudes and safety climate. Specifically it is intended: (a) to test the instruments; (b) to identify the essential dimensions of the safety climate in the airport ground handling companies; (c) to assess the quality of the differences in the safety climate for each company and its relation to the accident rate; (d) to analyse the relationship between attitudes and safety climate; and (e) to evaluate the influences of situational and personal factors on both safety climate and attitude. The study sample consisted of 166 subjects from three airport companies. Specifically, this research was centered on ground handling departments. The factor analysis of the safety climate instrument resulted in six factors which explained 69.8% of the total variance. We found significant differences in safety attitudes and climate in relation to type of enterprise.

  8. Pharmacokinetics, safety, and tolerability of phentermine in healthy participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist.

    PubMed

    Addy, Carol; Jumes, Patricia; Rosko, Kimberly; Li, Susie; Li, Hankun; Maes, Andrea; Johnson-Levonas, Amy O; Chodakewitz, Jeffrey; Stoch, S Aubrey; Wagner, John A

    2009-10-01

    This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC(0-24 h) in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for phentermine AUC(0-24 h) in the presence/absence of taranabant 0.5 mg and 2 mg were 1.08 (0.99, 1.17) and 1.04 (0.98, 1.10), respectively. No significant differences in blood pressure and heart rate were observed with any treatment versus placebo. Coadministration of taranabant 0.5 mg, 1 mg, and 2 mg with phentermine was well tolerated with no pharmacokinetic interaction and did not result in meaningful changes in blood pressure or heart rate versus placebo.

  9. Safety, tolerability and pharmacokinetics of phenoprolamine hydrochloride floating sustained-release tablets in healthy Chinese subjects.

    PubMed

    Zhao, Libo; Yang, Xiaoyan; Xu, Rong; Wu, Jianhong; Gu, Shifen; Zhang, Li; Gong, Peili; Chen, Hui; Zeng, Fandian

    2009-07-30

    The present study was designed to assess the safety, tolerability and pharmacokinetics of phenoprolamine hydrochloride floating sustained tablets (PHFST) in healthy Chinese subjects. 116 volunteers were randomized into single- or multiple-dose groups for oral administration 30-240 mg of PHFST once or 60-120 mg twice daily. Safety and tolerability were appraised by monitoring adverse events and laboratory parameters. Pharmacokinetics was assessed by determining the plasma concentrations of phenoprolamine hydrochloride with a validated HPLC method. In single-dose studies, no severe adverse events were observed in volunteers, and all adverse events were mild; the percentages of treatment-emergent events judged to be possibly related to the drug were 3/6 in the 240 mg dose group, 1/6 in the 180-210 mg dose groups, and none in the 30-150 mg dose groups; system exposure (AUC, C(max)) increased with respect to dose at 30-120 mg, whereas AUC raised disproportionately with dose escalating from 120 to 240 mg; the absorption of phenoprolamine hydrochloride was unaffected by food. In multiple studies, no safety concerns were revealed up to 7 days; steady-state plasma concentration was achieved after approximately 4-5 days of repeated twice-daily dosing. PHFST is safe and well tolerated in healthy Chinese subjects. The mean C(max) of PHFST is proportional to dose, but not the AUC. Oral dosing regimen selected for subsequent Phase II/III clinical trials was 60 mg of PHFST, b.i.d., and dose up to 120 mg, b.i.d. - may be used to achieve better antihypertensive effect.

  10. Pre-formulation characterization and pharmacokinetic evaluation of resveratrol

    NASA Astrophysics Data System (ADS)

    Robinson-Barnes, Keila Delores

    Resveratrol, a natural compound found in grapes has potential chemotherapy effects but very low oral bioavailability in humans. The objectives of this study are to quantitatively characterized and understand the physiochemical properties and the pharmacokinetic evaluation of resveratrol. Solubility of resveratrol was measured in 10 common solvents at 25°C using HPLC. The solution state pH stability of resveratrol was assessed in various USP buffers ranging from pH 2-10 for 24 hours at 37 °C. Human plasma protein binding was determined using ultracentrifugation technique. Stability of resveratrol in human and rat plasma was also assessed at 37°C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50 mug/mL. Samples were analyzed for resveratrol concentration up to 96 hours. A group (n=8) of jugular vein-cannulated adult male Sprague-Dawley rats were evaluated and received intravenous dose of 20 mg/kg resveratrol. Serial blood samples were collected up to 8 hours after the dose. Plasma concentrations of resveratrol were measured by an established LC-MS/MS method. Pharmacokinetic parameters were assessed using noncompartmental methods. Resveratrol is more soluble in alcohol and PEG-400, and stable in acidic pH. It binds highly to plasma proteins, and degrades slower in human then rat plasma. Resveratrol exhibits bioexponential disposition after intravenous administration and has a short elimination half-life. Resveratrol displays bioexponential disposition following intravenous administration. The estimated mean maximum concentration was 1045.5 ng/mL and rapidly dropped below 100 ng/mL within 30 minutes. The area under the concentration time curve (AUC) for resveratrol was 13888.7 min*ng/mL The mean terminal elimination half-life was 50.9 minutes. The mean total body clearance (Cl) and volume of distribution of trans-resveratrol were 1711.9mL/min/kg and 91087.8 mL/kg, respectively. Pre

  11. Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients ▿

    PubMed Central

    Michael, Claudia; Bierbach, Uta; Frenzel, Katrin; Lange, Thoralf; Basara, Nadezda; Niederwieser, Dietger; Mauz-Körholz, Christine; Preiss, Rainer

    2010-01-01

    The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher Cmax values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years. PMID:20547816

  12. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    SciTech Connect

    Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

    2014-05-15

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  13. Development of a simple chromatographic method for the determination of piracetam in human plasma and its pharmacokinetic evaluation.

    PubMed

    Barkat, K; Ahmad, M; Minhas, M U; Malik, M Z; Sohail, M

    2014-07-01

    The objective of study was to develop an accurate and reproducible HPLC method for determination of piracetam in human plasma and to evaluate pharmacokinetic parameters of 800 mg piracetam. A simple, rapid, accurate, precise and sensitive high pressure liquid chromatography method has been developed and subsequently validated for determination of piracetam. This study represents the results of a randomized, single-dose and single-period in 18 healthy male volunteers to assess pharmacokinetic parameters of 800 mg piracetam tablets. Various pharmacokinetic parameters were determined from plasma for piracetam and found to be in good agreement with previous reported values. The data was analyzed by using Kinetica® version 4.4 according to non-compartment model of pharmacokinetic analysis and after comparison with previous studies, no significant differences were found in present study of tested product. The major pharmacokinetic parameters for piracetam were as follows: t1/2 was (4.40 ± 0.179) h; Tmax value was (2.33 ± 0.105) h; Cmax was (14.53 ± 0.282) µg/mL; the AUC(0-∞) was (59.19 ± 4.402) µg · h/mL. AUMC(0-∞) was (367.23 ± 38.96) µg. (h)(2)/mL; Ke was (0.16 ± 0.006) h; MRT was (5.80 ± 0.227) h; Vd was (96.36 ± 8.917 L). A rapid, accurate and precise high pressure liquid chromatography method was developed and validated before the study. It is concluded that this method is very useful for the analysis of pharmacokinetic parameters, in human plasma and assured the safety and efficacy of piracetam, can be effectively used in medical practice. © Georg Thieme Verlag KG Stuttgart · New York.

  14. A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants.

    PubMed

    Leroux, Stéphanie; Roué, Jean-Michel; Gouyon, Jean-Bernard; Biran, Valérie; Zheng, Hao; Zhao, Wei; Jacqz-Aigrain, Evelyne

    2016-11-01

    Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  15. A multi-center, randomized, double-blind, parallel, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for the treatment of fever in critically ill and non-critically ill adults

    PubMed Central

    2010-01-01

    Introduction Hospitalized patients are often unable to ingest or tolerate oral antipyretics and recently an aqueous formulation of intravenous (IV) ibuprofen was approved by the US-FDA for the reduction of fever in adults. Methods We evaluated IV ibuprofen to reduce fever exceeding 101.0°F, measured as the percentage of subjects achieving a temperature <101.0°F at four hours after a single dose of IV ibuprofen vs. placebo. Secondary evaluations included the effect on temperature at 24 hours. Nine sites randomized patients to receive either a placebo or IV ibuprofen (100, 200, or 400 mg), and patients were given four hours for six doses. Subjects were excluded for platelet count <30 k and/or creatinine >3.0 mg/dL. Results At entry, there were no significant baseline differences between the IV ibuprofen group and placebo, n = 120. At four hours, the number (percentage) with T<101.0°F was: Placebo n = 9/28 (32%); 100 mg IV ibuprofen n = 19/31 (61%), P = 0.0264; 200 mg IV ibuprofen n = 21/30 (70%) P = 0.0043; 400 mg IV ibuprofen n = 24/31 (77%) P = 0.0005. A total of 53/120 patients (44%) were prospectively defined as critically ill at baseline and similar temperature reductions were observed in this subgroup. There were no statistically significant differences between treatment groups or when compared to placebo in transfusion, bleeding, renal failure or mortality. Conclusions All doses of IV ibuprofen tested reduced fever at four hours and throughout the first 24 hours of dosing. The 400 mg dose was effective in lowering temperature to normal and maintaining this over the first 24 hours of dosing. IV ibuprofen was effective in reducing fevers in critically ill and non-critically ill groups. Following 24 hours of administration of IV ibuprofen, no clinically significant differences in any safety parameter including renal function or bleeding occurred through the 28-day follow-up period. Trial registrations Clinicaltrials.gov registration number: NCT01131000. PMID

  16. Intravenous topiramate: safety and pharmacokinetics following a single dose in patients with epilepsy or migraines taking oral topiramate.

    PubMed

    Clark, Anne M; Kriel, Robert L; Leppik, Ilo E; White, James R; Henry, Thomas R; Brundage, Richard C; Cloyd, James C

    2013-06-01

    Although topiramate is widely prescribed for epilepsy and migraine, there is no intravenous product. We have developed an injectable topiramate formulation in which the drug is solubilized in a cyclodextrin matrix, Captisol(®) (Ligand Pharmaceuticals, Inc., La Jolla, CA). Our long-term goal is to evaluate intravenous topiramate for the treatment of neonatal seizures. Prior to studies in newborns, we carried out an investigation of injectable topiramate's safety and pharmacokinetics in adult patients. Twenty adult volunteers with epilepsy or migraine on stable, on maintenance topiramate therapy were given 25 mg of a stable-labeled intravenous topiramate over 10 min, followed by their usual oral doses. Vital signs were taken, electrocardiography studies (ECGs) were recorded, and the infusion sites were periodically examined prior to and up to 24 h after dosing. Blood samples were collected prior to administration and serially for 96 h thereafter. Plasma concentrations of both stable-labeled and regular topiramate were measured using liquid chromatography-mass spectrometry (LC-MS). Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, U.S.A.). Seven patients experienced one or more of the following minor adverse events including nausea and vomiting (1), tingling around the lips (1), paresthesia in the arms and legs (1), and a mild vasovagal response with intravenous catheter placement (1). Included in the adverse events were four patients with epilepsy who had seizures consistent with their histories. There were no changes in heart rate, blood pressure, or ECG results, and there were no infusion site reactions. Pharmacokinetic parameters (mean ± standard deviation [SD]) determined following the intravenous dose included absolute bioavailability: 110 ± 16%, distribution volume: 0.79 ± 0.22 L/kg, clearance: 2.03 ± 1.07 L/h, and elimination half-life: 27.6 ± 9.7 h. Distribution volume

  17. Pharmacokinetics, safety, and hydrolysis of oral pyrroloquinazolinediamines administered in single and multiple doses in rats.

    PubMed

    Li, Qigui; Kozar, Michael P; Shearer, Todd W; Xie, Lisa H; Lin, Ai J; Smith, Kirsten S; Si, Yuanzheng; Anova, Lalaine; Zhang, Jing; Milhous, Wilbur K; Skillman, Donald R

    2007-08-01

    Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng.h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng.h/ml) and one-half (1,381 ng.h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.

  18. Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants

    PubMed Central

    Benjamin, Daniel K; Smith, P Brian; Arrieta, Antonio; Castro, Lisa; Sánchez, Pablo J; Kaufman, David; Arnold, Leah J; Kovanda, Laura L; Sawamoto, Taiji; Buell, Donald N; Hope, William W; Walsh, Thomas J

    2010-01-01

    Due to the risk of central nervous system infection, relatively high weight-based echinocandin dosages may be required for successful treatment of invasive candidiasis and candidemia in young infants. This open-label study assessed safety and pharmacokinetics of micafungin in 13 young infants (> 48 hours of age and < 120 days of life) with suspected candidemia or invasive candidiasis. Infants weighing ≥ 1,000 g and < 1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4 to 5 days. Mean baseline weight and gestational age were 2101 g and 688 g, and 30 weeks and 25 weeks, in the 7 and 10 mg/kg/day groups, respectively. Median pharmacokinetic values for the 7 and 10 mg/kg/day groups, respectively, were: AUC0–24, 258.1 and 291.2 μg•h/ml; Clss/wt, 0.45 and 0.57 ml/min/kg; Cmax, 23.3 and 24.9 μg/ml; and Vdss/wt, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day were well tolerated and provided exposure that was demonstrated in animal model to be adequate for central nervous system coverage. PMID:19890251

  19. Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment.

    PubMed

    Gupta, Samir K; Kantesaria, Bhavna; Wang, Zaiqi

    2007-10-01

    Desloratadine, a nonsedating histamine H(1)-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6- to 6.5-fold greater than in other subjects with normal liver function. Eleven treatment-related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.

  20. 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.

  1. 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

  2. Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.

    PubMed

    Zuurmond, Anne-Marie; Koudijs, Angela; van El, Benno; Doornbos, Robert P; van Manen-Vernooij, Babs C T; Bastiaans, Jacqueline H M W; Penninks, André H; van Bilsen, Jolanda H M; Cnubben, Nicole H P; Degroot, Jeroen

    2011-04-01

    Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure.

  3. Pharmacokinetic evaluation and antitumor activity of 2-methoxyestradiol nanosuspension.

    PubMed

    Du, Shuzhang; Zhu, Ling; Du, Bin; Shi, Xiufang; Zhang, Zhenzhong; Wang, Shuyu; Zhang, Chaofeng

    2012-04-01

    The aim of the present study was to evaluate the pharmacokinetic and antitumor activity of 2-methoxyestradiol (2-ME) nanosuspension relative to 2-ME solution both in vitro and in vivo. The pharmacokinetics of 2-ME administered either as a nanosuspension or as a solution were compared after I.V. administration to rats. In plasma, 2-ME nanosuspension exhibited a significantly (p < 0.01) reduced C(max) (1022.8 ± 467.4 ng/mL versus 2559.2 ± 775.8 ng/mL) and AUC(0-240min) (41566.8 ± 965.5 ng/mL min versus 79557.7 ± 256.2 ng/mL min), and a significantly (p < 0.01) greater volume of distribution (3.18-fold), clearance (1.85-fold), and elimination half-life (156.6 ± 33.5 min versus 70.0 ± 22.6 min) compared to the 2-ME solution. Methyl tetrazolium (MTT) assay showed that nanosuspension could significantly enhance the cytotoxicity of 2-ME on EC9706 cells in vitro. After 72 h exposure, the IC(50) value of 2-ME nanosuspension was much lower than that of 2-ME solution (1.81 ± 0.15 μmol/L versus 4.14 ± 0.30 μmol/L). Studies on BALB/c mice with EC9706 solid tumors demonstrated significantly greater inhibition of tumor growth following treatment with 2-ME nanosuspension than 2-ME solution at the same dosage. These results suggest that the delivery of 2-ME nanosuspension is a promising approach for the treatment of tumors.

  4. Safety, Tolerability, and Pharmacokinetics of Micafungin (FK463) in Febrile Neutropenic Pediatric Patients

    PubMed Central

    Seibel, Nita L.; Schwartz, Cindy; Arrieta, Antonio; Flynn, Patricia; Shad, Aziza; Albano, Edith; Keirns, James; Lau, Wendi M.; Facklam, David P.; Buell, Donald N.; Walsh, Thomas J.

    2005-01-01

    Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients ≥9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age. PMID:16048942

  5. Pharmacokinetic and pharmacodynamic evaluation of linagliptin in African American patients with type 2 diabetes mellitus

    PubMed Central

    Friedrich, Christian; Glund, Stephan; Lionetti, Dominick; Kissling, C James; Righetti, Julian; Patel, Sanjay; Graefe-Mody, Ulrike; Retlich, Silke; Woerle, Hans-Juergen

    2013-01-01

    Aim This was an open label, multicentre phase I trial to study the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in African American patients with type 2 diabetes mellitus (T2DM). Methods Forty-one African American patients with T2DM were included in this study. Patients were admitted to a study clinic and administered 5 mg linagliptin once daily for 7 days, followed by 7 days of outpatient evaluation. Results Primary endpoints were area under the plasma concentration–time curve (AUC), maximum plasma concentration (Cmax) and plasma DPP-4 trough inhibition at steady-state. Linagliptin geometric mean AUC was 194 nmol l−1 h (geometric coefficient of variation, 26%), with a Cmax of 16.4 nmol l−1 (41%). Urinary excretion was low (0.5% and 4.4% of the dose excreted over 24 h, days 1 and 7). The geometric mean DPP-4 inhibition at steady-state was 84.2% at trough and 91.9% at maximum. The exposure range and overall pharmacokinetic/pharmacodynamic profile of linagliptin in this study of African Americans with T2DM was comparable with that in other populations. Laboratory data, vital signs and physical examinations did not show any relevant findings. No safety concerns were identified. Conclusions The results of this study in African American patients with T2DM support the use of the standard 5 mg dose recommended in all populations. PMID:23331248

  6. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men

    PubMed Central

    Basaria, Shehzad; Collins, Lauren; Dillon, E. Lichar; Orwoll, Katie; Storer, Thomas W.; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda

    2013-01-01

    Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. Methods. In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should

  7. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men.

    PubMed

    Basaria, Shehzad; Collins, Lauren; Dillon, E Lichar; Orwoll, Katie; Storer, Thomas W; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda; Bhasin, Shalender

    2013-01-01

    Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. In this placebo-controlled study, 76 healthy men (21-50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone-binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function

  8. Pharmacokinetics and Safety of Triple Therapy with Vonoprazan, Amoxicillin, and Clarithromycin or Metronidazole: A Phase 1, Open-Label, Randomized, Crossover Study.

    PubMed

    Sakurai, Yuuichi; Shiino, Madoka; Okamoto, Hiroyuki; Nishimura, Akira; Nakamura, Koki; Hasegawa, Setsuo

    2016-09-01

    Vonoprazan (TAK-438) is a novel potassium-competitive acid blocker that inhibits gastric H(+), K(+)-ATPase. The objectives of this study were to evaluate the influence of triple therapy with vonoprazan-amoxicillin-clarithromycin or vonoprazan-amoxicillin-metronidazole on the pharmacokinetics of each component of the triple therapies (primary) and to evaluate the safety and tolerability of vonoprazan-based triple therapies (secondary) in healthy adults. In this single-center, phase 1, open-label, randomized, four-way crossover study, Helicobacter pylori-negative, healthy Japanese male subjects were randomly assigned to 1 of 4 treatment sequences in two cohorts (12 subjects per cohort). Each treatment sequence comprised four treatment periods separated by a washout period of 7 or 14 days. Pharmacokinetic parameters for vonoprazan, amoxicillin, clarithromycin and metronidazole in single therapy or triple therapies were assessed. All adverse events were recorded. Compared with single therapy, triple therapy with vonoprazan-amoxicillin-clarithromycin increased the area under the plasma concentration-time curve from time 0-12 h (AUC0-12) and maximum plasma concentration (C max) of plasma vonoprazan free base by 1.846- and 1.868-fold, respectively, and increased the AUC0-12 and C max of plasma clarithromycin by 1.450- and 1.635-fold, respectively. Triple therapy with vonoprazan-amoxicillin-metronidazole had no influence on the pharmacokinetics of vonoprazan or metronidazole. The pharmacokinetics of amoxicillin was not influenced by vonoprazan-based triple therapies. Seven adverse events were reported. Two subjects discontinued because of an adverse event (rash, liver function test abnormal); both events were considered to be study drug-related. In healthy Japanese male subjects, triple therapy with vonoprazan-amoxicillin-clarithromycin increased vonoprazan and clarithromycin exposure. The safety and tolerability profile of triple therapy with vonoprazan

  9. Relative bioavailability, food effect, and safety of the single-dose pharmacokinetics of omecamtiv mecarbil following administration of different modified-release formulations in healthy subjects

    PubMed Central

    Palaparthy, Rameshraja; Banfield, Christopher; Alvarez, Paco; Yan, Lucy; Smith, Brian; Johnson, Jessica; Monsalvo, Maria Laura; Malik, Fady

    2016-01-01

    Objective: Omecamtiv mecarbil is a novel small molecule that directly activates cardiac myosin and increases cardiac contractility without increasing cardiac myocyte intracellular calcium. This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil. Methods: This was a phase 1, randomized, open-label, 4-way crossover, incomplete block-design study evaluating 5 MR formulations of omecamtiv mecarbil vs. an immediate-release (IR) formulation. Materials: Healthy subjects were randomized to 1 of 30 possible sequences: within each sequence, subjects were assigned to receive a single 25-mg dose of 2 of the 6 possible formulations in the fasting and/or fed states. Results: 65 subjects were screened and enrolled; 5 were replacement subjects. Pharmacokinetic and safety data were analyzed from 62 and 63 subjects in the fasting and fed states, respectively. Compared with the IR formulation, median tmax was longer (0.5 vs. 2 – 10 hours), and mean Cmax was lower for all 5 MR formulations (262 vs. 34 – 78 ng/mL); t1/2,z was similar (18 – 21 hours). The relative bioavailability was high (> 75%) for three MR formulations but lower (< 65%) for the other two. Overall, the effect of food on omecamtiv mecarbil pharmacokinetics was minimal for four of the MR formulations. The pharmacokinetics of the inactive metabolites M3 and M4 were similar across all formulations. Conclusions: The relative bioavailability of omecamtiv mecarbil was high (> 75%) for 3 of the five MR formulations. Food had a marginal, nonclinically meaningful effect on the pharmacokinetics of the MR formulations of omecamtiv mecarbil. PMID:26709596

  10. Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion

    PubMed Central

    2012-01-01

    Background CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. Methods A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. Results No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. Conclusions This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000). PMID:23171508

  11. Glibenclamide transdermal patches: physicochemical, pharmacodynamic, and pharmacokinetic evaluations.

    PubMed

    Mutalik, S; Udupa, N

    2004-06-01

    In the present study, matrix type transdermal patches containing glibenclamide were prepared using different ratios of ethyl cellulose (EC)/polyvinylpyrrolidone (PVP) and Eudragit RL-100 (ERL)/Eudragit RS-100 (ERS) by solvent evaporation technique. The possible drug and polymer interaction was studied by infrared spectroscopy, differential scanning calorimetry, and HPTLC analysis. All the prepared formulations were subjected to physicochemical studies (thickness, weight variation, drug content, moisture content and uptake, and flatness), in vitro release and in vitro permeation studies through mouse skin. The results suggested that there was no interaction between drug and polymers. Variations in drug release/permeation profiles among the formulations studied were observed. The microphotographs obtained by scanning electron microscopy showed the formation of pores on the surface of the patches after in vitro skin permeation studies. Based on physicochemical and in vitro skin permeation studies, the formulations with EC:PVP (3:2) and ERL:ERS (4:1) were selected for in vivo experiments. The hypoglycemic activity of the patches in comparison with oral glibenclamide administration was studied for acute (24 h) and long-term (6 weeks) effect in both normal and streptozotocin-induced diabetic mice. Various biochemical parameters (serum levels of high-density lipoprotein-cholesterol, triglycerides, total cholesterol, alanine transaminase, aspertate transaminase, urea, and creatinine and liver protein and glycogen content) and histopathological (liver, pancreas and stomach) studies were carried out in diabetic mice after treating for 6 weeks. The patches were subjected to skin irritation test (by both visual observation and histopathological evaluation), oral glucose tolerance test and pharmacokinetic evaluation in mice. The results revealed that the patches successfully prevented the severe hypoglycemia in the initial hours, which is the major side effect associated with

  12. External Evaluation of Two Fluconazole Infant Population Pharmacokinetic Models.

    PubMed

    Hwang, Michael F; Beechinor, Ryan J; Wade, Kelly C; Benjamin, Daniel K; Smith, P Brian; Hornik, Christoph P; Capparelli, Edmund V; Duara, Shahnaz; Kennedy, Kathleen A; Cohen-Wolkowiez, Michael; Gonzalez, Daniel

    2017-09-11

    Fluconazole is an antifungal agent used for the treatment of invasive candidiasis, a leading cause of morbidity and mortality in premature infants. Population pharmacokinetics (PK) models of fluconazole in infants have been previously published by Wade et al. and Momper et al. Here we report the results of the first external evaluation of the predictive performance of both models. We used patient level data from both studies to externally evaluate both PK models. The predictive performance of each model was evaluated using the model prediction error (PE), mean prediction error (MPE), mean absolute prediction error (MAPE), prediction-corrected visual predictive check (pcVPC), and normalized prediction distribution errors (NPDE). The parameters of each model were re-estimated using both the external and merged datasets. When evaluated with an external data set, the model proposed by Wade et al. showed lower median PE, MPE, and MAPE (0.429 μg/mL, 41.9%, and 57.6%, respectively) compared to the model proposed by Momper et al. (2.45 μg/mL, 188%, and 195%, respectively). The majority of re-estimated parameters were within 20% of their respective original parameter values for all model evaluations. Our analysis determined that though both models are robust, the model proposed by Wade et al. had greater accuracy and precision than the model proposed by Momper et al., likely because it was derived from a patient population with a wider age range. This study highlights the importance of external evaluation of infant population PK models. Copyright © 2017 American Society for Microbiology.

  13. Safety, efficacy and pharmacokinetics of humanized anti-CD52 monoclonal antibody alemtuzumab in Japanese patients with relapsed or refractory B-cell chronic lymphocytic leukemia.

    PubMed

    Ishizawa, Kenichi; Fukuhara, Noriko; Nakaseko, Chiaki; Chiba, Shigeru; Ogura, Michinori; Okamoto, Akihiko; Sunaga, Yoshinori; Tobinai, Kensei

    2017-01-01

    To evaluate the safety, efficacy and pharmacokinetics of alemtuzumab in Japanese patients, we conducted a phase I study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. Six patients received alemtuzumab by intravenous infusion every other day three times a week for 12 weeks. The dose was gradually escalated on daily basis (3, 10 and then 30 mg) until the patient tolerated. The primary objective was to evaluate the safety of alemtuzumab in Japanese patients and the secondary objectives were to evaluate the overall response rate and the pharmacokinetics. The major treatment-emergent adverse events were anemia, neutropenia (6/6 patients each) and thrombocytopenia (5/6 patients) in hematologic adverse events, and nausea, vomiting, decreased appetite, cytomegalovirus test positive and pyrexia (4/6 patients) in non-hematologic adverse events. As serious adverse events, cytomegalovirus infection, pulmonary tuberculosis and diffuse large B-cell lymphoma were reported in 1/6 patient each. The overall response rate was 33% (95% confidence interval: 4-78) (1/6 patient each achieved complete response and partial response, respectively) and 3/6 patients had stable disease and 1/6 patient had progressive disease. The median time to response was 2.9 months. After last intravenous dosing (Week 12) of alemtuzumab 30 mg every other day three times a week, Cmax, tmax, AUC0-τ and t1/2 were higher and CL and Vss were lower than the values observed after the first dose. The efficacy, safety and pharmacokinetics results observed with alemtuzumab in Japanese patients were generally similar to those reported in overseas clinical studies. Alemtuzumab at 30 mg by intravenous infusion every other day three times a week for 12 weeks should be safe and effective similarly in Japanese B-cell chronic lymphocytic leukemia patients. NCT00923182. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Retrospective Evaluation of Milrinone Pharmacokinetics in Children With Kidney Injury.

    PubMed

    Gist, Katja M; Mizuno, Tomoyuki; Goldstein, Stuart L; Vinks, Alexander

    2015-12-01

    Milrinone is an inotropic agent with vasodilating properties used in the treatment of ventricular dysfunction. Milrinone is predominantly eliminated by the kidneys and accumulates in the setting of acute kidney injury (AKI). The purpose of this study was to evaluate milrinone pharmacokinetics in children with AKI with or without continuous renal replacement therapy (CRRT). Retrospective collection of milrinone therapeutic drug monitoring data in patients with AKI, including those requiring CRRT, through chart review from January 2008 to March 2014. Pharmacokinetic (PK) data were analyzed by Bayesian estimation using a pediatric population PK model (MW/Pharm). Clearance estimates were allometrically scaled to body weight. Data on 11 patients were available for analysis. Three patients required CRRT. Milrinone concentrations during continuous infusion varied 30-fold and ranged from 44 to 1343 ng/mL. Of the 33 samples obtained in 11 patients, 24 were outside the target range (72.7%), with 16 (48.5%) above and 8 (24.2%) below. Patients with AKI had significantly lower milrinone clearance (4.72 ± 2.26 L/h per 70 kg) compared with published data in patients without AKI. There was large between-patient variability in milrinone clearance (range: 2.91-13.6 L/h per 70 kg). Clearance in patients on CRRT ranged from 2.8 to 7.19 L/h per 70 kg. A significant correlation between milrinone clearance and estimated creatinine clearance was observed (r = 0.70, P = 0.0097). Allometrically scaled milrinone clearance was lower in the youngest patients (younger than 2 years), suggestive of ongoing renal maturation and existing AKI. Pediatric patients with AKI have significantly lower milrinone clearance compared with published data in patients without AKI. Large variability was noted in milrinone concentrations, and they were frequently outside the target range. The large between-patient variability in milrinone concentrations suggests that dosing regimens should be individualized in

  15. Pharmacokinetics and safety of 0.5% ivermectin lotion for head louse infestations.

    PubMed

    Hazan, Lydie; Berg, Jeffrey E; Bowman, James P; Murray, John V; Ryan, William G

    2013-01-01

    The safety of a novel 0.5% ivermectin lotion (IVL) and potential for ivermectin absorption after application was investigated in an open-label study in young children, and a human repeat insult patch test (HRIPT) and cumulative irritation test (CIT) assessed any potential for cumulative dermal irritation and contact sensitization. In the pharmacokinetic and safety study, 30 head louse-infested children ages 6 months to 3 years received a 10-minute application of IVL on day 1. Blood was collected before application; 0.5, 1, and 6 hours after rinsing; and on days 2 and 8. Samples from 20 subjects were assayed for ivermectin (test sensitivity 0.05 ng/mL). Liver panel and complete blood counts were completed for all subjects. For the HRIPT/CIT, occlusive patches containing IVL or vehicle control lotion (CL) were repeatedly applied to 220 healthy adult subjects to assess contact sensitization; for cumulative dermal irritation testing, additional patches with normal saline and sodium dodecyl sulfate (SDS) were applied to 36 subjects. In the open-label study, all detected ivermectin plasma concentrations were <1 ng/mL. No safety signals emerged, and treatment was well tolerated. In the HRIPT/CIT, IVL was significantly less irritating than normal saline and SDS, with no evidence of dermal irritation or sensitization in human skin. IVL was safe when applied topically, absorption was de minimus, there was no evidence of irritation or sensitization from repeated exposures, and results support the safety of topical IVL use in children as young as 6 months. © 2012 Wiley Periodicals, Inc.

  16. Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines.

    PubMed

    Lionetto, Luana; Casolla, Barbara; Mastropietri, Fabiola; D'Alonzo, Lidia; Negro, Andrea; Simmaco, Maurizio; Martelletti, Paolo

    2012-08-01

    Migraine is a multifactorial neurovascular disorder characterized by recurrent episodes of disabling pain attacks, accompanied with gastrointestinal, neurological systems dysfunction. The pharmacologic treatment of migraine is classically divided in the management of the acute attack and preventive strategies. Acute treatments consist of triptan, ergot, opioid, antiemetic and NSAIDs. This article discusses pharmacodynamics and pharmacokinetics of zolmitriptan . The data were obtained by searching the following keywords in MEDLINE: zolmitriptan, pharmacokinetics, pharmacodynamics, triptans, migraine, menstrual-related migraine, cluster headache, relatively to the period 1989 - 2012. Zolmitriptan has been considered effective treatment in the acute phase of migraine, menstrual-related migraine and cluster headache attacks. Pharmacokinetic parameters may vary as a consequence of gender differences, inter- and intra-subjects variability and delivery system. Zolmitriptan was developed with the aim of obtaining a lipophilic compound in order to be more rapidly absorbed and centrally active. Pharmacologically, pharmacokinetic parameters are responsible for its wide efficacy and the limited adverse effect profile.

  17. Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

    PubMed

    Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

    2017-02-01

    Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and maximum plasma concentration (C max) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

  18. Raltegravir for HIV-1 infected children and adolescents: efficacy, safety, and pharmacokinetics

    PubMed Central

    Larson, Kajal B; King, Jennifer R; Acosta, Edward P

    2013-01-01

    Raltegravir was the first HIV integrase strand-transfer inhibitor to be approved by the US FDA, in October 2007, for the treatment of HIV-1 infection in combination with other antiretroviral agents. Raltegravir can be used in treatment-naïve and -experienced patients, as well as for the treatment of multidrug-resistant infection. Raltegravir exists in two formulations: a film-coated tablet administered orally at 400 mg twice daily, and a chewable tablet administered orally at 300 mg twice daily. In 2011, raltegravir was also approved for the treatment of children and adolescents, ages 2–18 years. For adolescents (ages 12–18 years), the recommended dose is 400 mg twice daily (film-coated tablet). If children (ages 6–12 years) weigh at least 25 kg, the film-coated tablet is recommended at 400 mg twice daily. Otherwise, patients receive the chewable tablet according to weight-based dosing at approximately 6 mg/kg/dose. Studies are ongoing for children ages 4 weeks to 2 years, and preliminary efficacy and safety data are promising. This article reviews current studies on the efficacy, safety, and pharmacokinetics of raltegravir in the pediatric population and the challenges of treating HIV in children and adolescents. PMID:24600298

  19. Safety and Pharmacokinetics of Multiple Dose myo-Inositol in Preterm Infants

    PubMed Central

    Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Nolen, Tracy L.; Watterberg, Kristi L.; Oh, William; Goedecke, Michael; Ehrenkranz, Richard A.; Fennell, Timothy; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; Lacy, Conra Backstrom; Walsh, Michele C.; Carlo, Waldemar A.; Sánchez, Pablo J.; Bell, Edward F.; Shankaran, Seetha; Carlton, David P.; Chess, Patricia R.; Higgins, Rosemary D.

    2016-01-01

    BACKGROUND Preterm infants with RDS given inositol had reduced BPD, death and severe ROP. We assessed the safety and pharmacokinetics(PK) of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS Infants ≤29wks GA (n=122, 14 centers) were randomized and treated with placebo or inositol at 10, 40 or 80mg/kg/day. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 weeks, 34weeks PMA or discharge. Serum collection employed a sparse sampling population PK design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS At 80mg/kg/day mean serum levels reached 140mg/L, similar to Hallman’s findings. Levels declined after 2 weeks, converging in all groups by 6 wks. Analyses showed a mean volume of distribution 0.657 L/kg, clearance 0.058 L/kg/hr, and half-life 7.90 hr. Adverse events and co-morbidities were fewer in the inositol groups, but not significantly so. CONCLUSIONS Multiple dose inositol at 80mg/kg/day was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a Phase 3 trial. PMID:27074126

  20. [Evaluation of pharmacokinetic drug-drug-interactions. Critical considerations of the relevance of pharmacokinetic drug-drug interactions of proton pump inhibitors in self medication].

    PubMed

    Petersen, Karl-Uwe

    2011-08-01

    Mechanisms and evaluation of pharmacokinetic drug interactions are discussed in general, including mechanisms beyond the hepatic phase-I reactions, and especially for the example of proton pump inhibitors (PPI), preferentially omeprazole. Particular attention is paid to the use of PPI as self-prescribed drugs. The sequelae of pharmacokinetic drug interactions can be serious. However, only the evidence of clinical consequences will convert such an interaction from a laboratory finding into a possible adverse effect. Without this, interacting drugs can still be co-administered if the specific characteristics of the concerned drugs, quantitative aspects of the interaction, and especially severity and frequency of possible clinical correlates are taken into consideration. It is encouraging that the laboratory findings reported for the PPI--in vitro or ex vivo from volunteer studies--have hardly found equivalents in clinical consequences. As of today, this is also true of the widely discussed interaction with clopidogrel. Regarding the safety of use of PPI as self-prescribed drugs, it also needs to be emphasized that a sizable number of interactions reported for omeprazole and/or pantoprazole were observed at higher dose levels than the 20 mg licensed for self medication. In conjunction with the temporal limitation of PPI self-prescription (14 days), it can be expected that pharmacokinetic drug interactions will generally be no critical factor in the usage of PPI in self-medication. However clinically relevant interactions can occur, e.g. when PPI are combined with extracts from St. John's wort, methotrexat or some inhibitors of HIV-protease with pH-dependent absorption.

  1. Pharmacokinetics, Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1–Infected Children Aged 2 Through 18 Years

    PubMed Central

    Nachman, Sharon; Zheng, Nan; Acosta, Edward P.; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Wenning, Larissa; Spector, Stephen A.; Frenkel, Lisa M.; Alvero, Carmelita; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew; Moultrie, Harry; Kindra, Gurpreet; Sanders, Margaret Ann; Williams, Ruth; Jensen, Jennifer; Acevedo, Midnela; Fabregas, Lizbeth; Jurgrau, Andrea; Foca, Marc; Higgins, Alice; Deville, Jaime G.; Nielsen-Saines, Karin; Carter, Michele F.; Swetnam, John; Wilson, Joan; Donnelly, Margaret; Akleh, Siham; Rigaud, Mona; Kaul, Aditya; Patel, Nehali; Gaur, Aditya; Utech, L. Jill; Cardoso, Edmundo; Moreira, Ana Maria; Santos, Breno; Bobat, Raziya; Mngqibisa, Rosie; Burey, Marlene; Abadi, Jacob; Rosenberg, Michael; Luzuriaga, Katherine; Picard, Donna; Pagano-Therrien, Jessica; Dittmer, Sylvia; Ndiweni, Hilda Ntatule; Patel, Amisha; DelRey, Michelle; McMullen-Jackson, Chivon; Paul, Mary E.; Melvin, Ann; Venema-Weiss, Corry; Lane, Jenna; Beneri, Christy; Ferraro, Denise; Infanzon, Erin; McAuley, James B; Aziz, Mariam; McNichols, Maureen; Pelton, Stephen; McLaud, Deb; Clarke, Diana; Zeichner, Steven; Akar, Arezou; Thompson, Deidre; Douglas, Steven D.; Rutstein, Richard M.; Vincent, Carol A.; Vachon, Mary Elizabeth; Cavallo, Martha; Purswani, Murli Udharam; Masheto, Gaerolwe; Ogwu, Anthony; Kakhu, Tebogo; Viani, Rolando M.; Darcey, Anita,; Norris, Kimberly; Burchett, Sandra K.; Kneut, Catherine; Karthas, Nancy; Casey, Denise; Emmanuel, Patricia; Lujan-Zilbermann, Jorge; Rana, Sohail; Houston, Patricia; Mengistab, Mulu; Rathore, Mobeen; Mirza, Ayesha; Gayton, Tabetha; Barr, Emily; Dunn, Jennifer; Hahn, Kerry; Eysallenne, Zulma; Howard, F. Sholar; Graham, Kathleen; Negra, Marinella Della; Queiroz, Wladimir; Lian, Yu Ching; Wara, Diane; Ruel, Ted; VanDyke, Russell; Reilly, Patricia; Bradford, Sheila; van Rensburg, Anita Janse; Dobbels, Els; Bester, Marietjie; Bamji, Mahrukh; Paul, Santa; Sarza, Mirala; Kovacs, Andrea; Homans, James; Spencer, LaShonda; Hofer, Cristna; Abreu, Thalita; Oliveira, Ricardo; Joao, Esau C.; Pinto, Jorge; Ferreira, Flavia; Kakehasi, Fabiana; Cervi, Maria Celia; Isaac, Marcia De Lima; Losso, Marcelo H.; Stankievich, Erica; Foradori, Irene; Tucker, Diane; Church, Joseph; Belzer, Marvin; Hopkins, Johns; Ellen, Jonathan; Agwu, Allison; Laurel, Borkovic

    2014-01-01

    Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)–infected youth. Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction between baseline and week 24. Results. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%). Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. Clinical Trials Registration NCT00485264. PMID:24145879

  2. Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man.

    PubMed

    Brecht, H M; Adamus, W S; Heuer, H O; Birke, F W; Kempe, E R

    1991-01-01

    Platelet-activating factor (PAF) is a unique phospholipid mediator with multifunctional properties. Evidence generated in experimental studies suggests that PAF plays a pathogenetic role in anaphylactic, inflammatory and immunogenic reactions. Apafant (WEB 2086, CAS 105219-56-5), a novel synthetic PAF receptor antagonist, was administered to a total of 101 healthy volunteers within 5 studies to investigate its pharmacologic activity, pharmacokinetic behaviour and safety profile. Pharmacologic activity was monitored by inhibition of 5 x 10(-8) mol/l PAF-induced platelet aggregation ex vivo. The following treatment schedules were studied: oral single dose 1.25 to 400 mg; oral multiple dose 100 mg t.i.d. over 7 days; i.v. infusion 0.5 to 50 mg (over 30 min); inhalative administration up to 1.0 mg. PAF induced platelet aggregation was virtually completely inhibited by single oral doses of 20 mg upwards, throughout during the multiple oral dose study, at all dose levels tested in the i.v. study and (significantly but not completely) at 0.5 and 1.0 mg in the inhalative study. Following oral administrations (capsules) apafant is absorbed rapidly (tmax 1 to 2 h), there is linear pharmacokinetics for the mean plasma concentrations of apafant measured by RIA as well as for the areas under the curve (AUCs). Approximately 60% of apafant is bound to plasma protein, the mean volume of distribution is 28 l, about 44% of an oral dose is excreted in the urine, the mean renal clearance is 192 ml/min. No accumulation of the drug occurred in volunteers with normal kidney function. No clinically relevant drug related adverse events or changes in laboratory or vital parameters such as blood pressure, heart rate, respiratory rate and ECG were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Safety, tolerability and pharmacokinetic properties of coadministered azithromycin and piperaquine in pregnant Papua New Guinean women.

    PubMed

    Moore, Brioni R; Benjamin, John M; Auyeung, Siu On; Salman, Sam; Yadi, Gumul; Griffin, Suzanne; Page-Sharp, Madhu; Batty, Kevin T; Siba, Peter M; Mueller, Ivo; Rogerson, Stephen J; Davis, Timothy Me

    2016-07-01

    The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of coadministered azithromycin (AZI) and piperaquine (PQ) for treating malaria in pregnant Papua New Guinean women. Thirty pregnant women (median age 22 years; 16-32 weeks' gestation) were given three daily doses of 1 g AZI plus 960 mg PQ tetraphosphate with detailed monitoring/blood sampling over 42 days. Plasma AZI and PQ were assayed using liquid chromatography-mass spectrometry and high-performance liquid chromatography, respectively. Pharmacokinetic analysis was by population-based compartmental models. The treatment was well tolerated. The median (interquartile range) increase in the rate-corrected electrocardiographic QT interval 4 h postdose [12 (6-26) ms(0) (.5) ] was similar to that found in previous studies of AZI given in pregnancy with other partner drugs. Six women with asymptomatic malaria cleared their parasitaemias within 72 h. Two apararasitaemic women developed late uncomplicated Plasmodium falciparum infections on Days 42 and 83. Compared with previous pregnancy studies, the area under the concentration-time curve (AUC0-∞ ) for PQ [38818 (24354-52299) μg h l(-1) ] was similar to published values but there was a 52% increase in relative bioavailability with each dose. The AUC0-∞ for AZI [46799 (43526-49462) μg h l(-1) ] was at least as high as reported for higher-dose regimens, suggesting saturable absorption and/or concentration-dependent tissue uptake and clearance from the central compartment. AZI-PQ appears to be well tolerated and safe in pregnancy. Based on the present/other data, total AZI doses higher than 3 g for the treatment and prevention of malaria may be unnecessary in pregnant women, while clearance of parasitaemia could improve the relative bioavailability of PQ. © 2016 The British Pharmacological Society.

  4. Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2.

    PubMed

    Bain, G; King, C D; Brittain, J; Hartung, J P; Dearmond, I; Stearns, B; Truong, Y P; Hutchinson, J H; Evans, J F; Holme, K

    2012-10-01

    The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

  5. Phase I Safety and Pharmacokinetics Study of Micronized Atovaquone in Human Immunodeficiency Virus-Infected Infants and Children

    PubMed Central

    Hughes, Walter; Dorenbaum, Alejandro; Yogev, Ram; Beauchamp, Belinda; Xu, Jing; McNamara, James; Moye, John; Purdue, Lynette; van Dyke, Russell; Rogers, Michael; Sadler, Brian; Group, The Pediatric Aids Clinical Trials

    1998-01-01

    A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 μg/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 μg/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day. PMID:9624466

  6. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans

    PubMed Central

    Manini, Alex F.; Yiannoulos, Georgia; Bergamaschi, Mateus M.; Hernandez, Stephanie; Olmedo, Ruben; Barnes, Allan J.; Winkel, Gary; Sinha, Rajita; Jutras-Aswad, Didier; Huestis, Marilyn A.; Hurd, Yasmin L.

    2015-01-01

    Objectives Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions. Conclusions CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse. PMID:25748562

  7. Practical considerations for nonclinical safety evaluation of therapeutic monoclonal antibodies

    PubMed Central

    Lynch, Carmel M; Hart, Bruce W

    2009-01-01

    Monoclonal antibodies (mAbs) are a well established class of therapeutics as evidenced by a large number of FDA approved mAbs for the treatment of cancers and autoimmune diseases. Monoclonal antibodies that are molecularly engineered for enhanced functions and pharmacokinetic properties are routinely being considered for development by many biotechnology companies. Safety evaluation of current generation of mAbs poses new challenges due to the highly complex nature of engineering aspects and variability induced by the diverse recombinant cell systems to generate them. This review provides a basic outline for nonclinical safety evaluation of therapeutic antibodies. Important considerations for planning a preclinical program, the types of nonclinical safety studies, and a general timeline for their conduct in relation to clinical trials are described. A list of relevant regulatory documents issued by government agencies is also provided. Adoption of these principles will greatly enhance the quality and relevance of the nonclinical safety data generated and will facilitate future development of mAb therapeutics. PMID:20046568

  8. Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics.

    PubMed

    Viele, M K; Weiskopf, R B; Fisher, D

    1997-04-01

    Recombinant human hemoglobin (OptroD; rHb1.1) is a genetically engineered protein produced in Escherichia coli. The two alpha-globin polypeptides are genetically joined, resulting in a stable tetramer that does not dissociate into dimers or monomers. Historically, infusion in humans of acellular hemoglobin preparations has resulted in renal toxicity. This study was performed to evaluate the safety and pharmacokinetics of rHb1.1 when infused in humans. After giving informed consent, 48 healthy male volunteers were randomly assigned to receive either 0.015-0.32 g/kg 5% rHb1.1 (n = 34) or an equivalent amount of 5% human serum albumin (HSA; n = 14) infused intravenously over 0.8-1.9 h. Serum creatinine, creatinine clearance, urine N-acetyl-beta-glucosaminidase, and serum rHb1.1 concentrations were measured before and at timed intervals after infusion. Postinfusion urine N-acetyl-beta-glucosaminidase activity did not exceed preinfusion values at any interval in either group. Serum creatinine did not differ from preinfusion values at 1 day, 2-3 days, or 7 days after infusion for either group. Creatinine clearance increased significantly for the HSA group 12 h after infusion (138 +/- 16 ml/min, means +/- SE) and in the rHb1.1 group 1 day after infusion (112 +/- 5 ml/min; P < 0.05). Values for creatinine clearance did not differ from preinfusion values for either group at any other postinfusion interval; serum creatinine and creatinine clearance did not differ between groups at any time. The amount of hemoglobin excreted in the urine did not exceed approximately 0.04% of the administered rHb1.1 dose in any volunteer. Plasma clearance of rHb1.1 decreased and half-life increased as a function of increasing plasma concentration (e.g., the half-life was 2.8 h at a plasma concentration of 0.5 mg/ml and 12 h at 5 mg/ml). The incidence of gastrointestinal symptoms, fever, and chills was greater after infusion of rHb1.1 than after HSA (P < 0.05). No evidence for rHb1.1-mediated

  9. Evaluation of Safety and Pharmacokinetics of Sodium 2,2 Dimethylbutyrate, a Novel Short Chain Fatty Acid Derivative, in a Phase 1, Double-Blind, Placebo-Controlled, Single- and Repeat-Dose Studies in Healthy Volunteers

    PubMed Central

    Perrine, Susan P.; Wargin, William A.; Boosalis, Michael S.; Wallis, Wayne J.; Case, Sally; Keefer, Jeffrey R.; Faller, Douglas V.; Welch, William C.; Berenson, Ronald J.

    2013-01-01

    Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel SCFA derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with one of four single dose levels (2, 5, 10 and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9–15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable PK profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies. PMID:21422239

  10. Safety, Tolerability, and Pharmacokinetic Profile of the Novel Translocator Protein 18 kDa Antagonist ONO-2952 in Healthy Volunteers.

    PubMed

    Suto, Fumitaka; Wood, Andrew T; Kobayashi, Michiyoshi; Komaba, Junji; Duffy, Kevin; Bruce, Mark

    2015-09-01

    To investigate safety, tolerability, and pharmacokinetic properties of single and multiple doses of novel translocator protein 18 kDa antagonist ONO-2952 in healthy subjects. Double-blind, placebo-controlled single (SAD) and multiple (MAD) dose escalation studies were conducted. Healthy men and women aged 18 to 55 years inclusive and without history of psychiatric disorders were eligible. Forty-eight volunteers received single doses of ONO-2952 (3, 10, 30, 100, 200, or 400 mg) or placebo under fasted conditions (SAD study), and 36 received ONO-2952 (30, 60, or 100 mg/d) or placebo for 21 consecutive days under fed conditions (MAD study). ONO-2952 10 and 200 mg were administered under fasted and fed conditions in the SAD study to investigate the effect of food on the absorption of ONO-2952. Safety assessments included adverse events, vital signs, 12-lead ECGs, and clinical laboratory evaluations. Plasma and urine pharmacokinetic profiles of ONO-2952 were determined. Across both studies, mean age ranged from 29.8 to 39.8 years, most participants were white, and the proportion of female volunteers was 52%. No treatment or dose-related trends in adverse events were observed. The most frequent adverse events were headache and presyncope (n = 2 each [SAD study]) and constipation and headache (n = 3 each [MAD study]). All headache and constipation episodes were possibly related to the study drug. Plasma ONO-2952 concentrations peaked 2.5 to 3.5 hours (SAD study) and 3.0 to 4.0 hours (MAD study) postdose. ONO-2952 systemic exposure increased less than dose proportionally under fasted conditions. Fed conditions significantly increased exposure compared with fasted conditions: geometric mean ratios of Cmax (90% CIs) were 229% (176-299 [10 mg]) and 778% (623-971 [200 mg]), and AUClast were 159% (131-192 [10 mg]) and 382% (288-506 [200 mg]). In the MAD study, the systemic exposure of ONO-2952 increased in a slightly greater than dose-proportional manner. Geometric mean

  11. Evaluation of the potential for a pharmacokinetic drug-drug interaction between armodafinil and ziprasidone in healthy adults.

    PubMed

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2014-10-01

    Armodafinil has been studied as adjunctive therapy for major depressive episodes associated with bipolar I disorder. This open-label, single-centre, 2-period study evaluated the effect of armodafinil, a moderate inducer of cytochrome-P450 (CYP) isoenzyme CYP3A4, on the pharmacokinetics and safety of ziprasidone, an atypical antipsychotic used to treat bipolar I disorder and metabolized in part by CYP3A4. Thirty-five healthy subjects received ziprasidone (20 mg) alone and after armodafinil pretreatment (titrated to 250 mg/day); of those, 25 were evaluable for pharmacokinetics. Pharmacokinetic parameters were derived from plasma concentrations of ziprasidone collected prior to and over the 48 h after each ziprasidone administration. Plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone, were also obtained after repeated daily dosing of armodafinil alone. Safety and tolerability were assessed. Systemic exposure to ziprasidone was similar following administration alone or after pretreatment with armodafinil, as assessed by mean peak plasma concentration (C max, 52.1 vs 50.4 ng/mL) and area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞, 544.6 vs 469.1 ng·h/mL). Geometric mean ratios of systemic exposure (ziprasidone alone: ziprasidone after pretreatment with armodafinil) were close to unity, with associated 90 % confidence intervals (CIs) within the range of 0.80-1.25 (C max, 0.97; 90 % CI, 0.87-1.08; AUC0-∞, 0.86; 90 % CI, 0.82-0.91). Adverse events were consistent with the known safety profiles of each agent. Systemic exposure to ziprasidone was not affected by pretreatment with armodafinil. Both drugs were generally safe and well tolerated under the conditions studied.

  12. Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesoterodine.

    PubMed

    Malhotra, B K; Wood, N; Sachse, R

    2009-09-01

    Fesoterodine, a new antimuscarinic agent for overactive bladder, undergoes immediate and extensive hydrolysis by nonspecific esterases to 5-hydroxymethyl tolterodine (5-HMT), the metabolite principally responsible for its antimuscarinic activity. Formation of 5-HMT does not require cytochrome P450 (CYP)-mediated metabolism, but its further metabolism and inactivation involves CYP3A4 and CYP2D6 isoenzymes. Subject age, gender, and race can play a key role in inter-subject variability in pharmacokinetics and thus efficacy and safety of drugs. This article examines the effects of age, gender, and race on the pharmacokinetics and pharmacodynamics of fesoterodine. Data from two randomized, double-blind, placebo-controlled, parallel-group trials in healthy subjects are presented: Study 1 investigated the effects of race (white vs. black men) and Study 2 investigated the effects of age (young vs. old men) and gender (elderly men vs. elderly women) on the pharmacokinetics and pharmacodynamics of single doses of fesoterodine 8 mg. In both studies, the primary endpoints were area under the concentration-time curve up to the last sample (AUC0-tz) and maximum concentration (Cmax) of 5-HMT in plasma. Pharmacodynamic variables included spontaneous salivary secretion (Studies 1 and 2) and residual urine volume (Study 2 only). The two studies included 5 groups of 16 subjects each (randomized 3 : 1 to fesoterodine or placebo): white men aged 18 - 45 years, black men aged 18 - 45 years (Study 1); young white men aged 18 - 40 years, elderly white men aged > 65 years, and elderly white women aged > 65 years (Study 2). There were no clinically meaningful differences in the primary endpoints between white and black subjects or between young white men, elderly white men, and elderly white women. Mean AUC0-tz was 70.7 ng/ml x h in whites and 64.1 ng/ml x h in blacks; mean Cmax was 6.1 and 5.5 ng/ml in whites and blacks, respectively. Mean AUC0-tz in young white men, elderly white men, and

  13. Assessment of drug accumulation in the evaluation of pharmacokinetic data.

    PubMed

    Meineke, I; Gleiter, C H

    1998-08-01

    The evaluation of drug accumulation is approached from a practical point of view. Estimates of accumulation indices as obtained from standard estimators-AUC, peak levels, and trough levels (RAUAUC Rmax and Rmin, respectively)-are compared and differences analyzed. The estimators are based on the concentration-time curve characteristics area under the concentration-time curve (AUC), maximum concentration, and trough level. Simulated data are used for the analysis, both noise-free and with random error added. The data are based on pharmacokinetic parameters derived from a clinical study. The numerical procedures can be reproduced by the interested reader with little effort. It is shown empirically that if Rmin, > RAUC then simple kinetic behavior cannot be safely assumed, but accumulation is a complex function of time. Rmax as obtained from the data and an estimate of this value based on time to peak concentration (tmax) and apparent elimination rate constant (lambda(z)) after a single dose and at steady state can then be compared in an attempt to exclude time-dependent kinetics. This new numerical procedure can provide valuable and even pivotal information regarding the accumulation kinetics of a compound under investigation. Recommendations on how to use the available concentration-time information to the best advantage are presented. It is concluded that the assessment of drug accumulation should not be confined to the calculation of just one estimate, because the three estimators RAUC, Rmax. and Rmin reflect different aspects of accumulation. Moreover, all information about accumulation should be carefully analyzed in the clinical context. This way the relevant accumulation can be identified for safe and efficacious drug treatment.

  14. The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development

    PubMed Central

    Walker, D K

    2004-01-01

    The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially. PMID:15563358

  15. Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial

    PubMed Central

    Noguchi-Shinohara, Moeko; Ono, Kenjiro; Hamaguchi, Tsuyoshi; Iwasa, Kazuo; Nagai, Toshitada; Kobayashi, Shoko; Nakamura, Hiroyuki; Yamada, Masahito

    2015-01-01

    The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state) and Study 2 (fed state)]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals. Trial Registration Trial Registration: UMIN-CTR UMIN000004997 PMID:25978046

  16. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects.

    PubMed

    Yu, Yanke; Logovinsky, Veronika; Schuck, Edgar; Kaplow, June; Chang, Min-Kun; Miyagawa, Takehiko; Wong, Nancy; Ferry, Jim

    2014-05-01

    E2212, a novel γ-secretase modulator, is under development for the treatment of Alzheimer's disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10-250 mg, double-blind, placebo-controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C-SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5-19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aβ(x-42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0-24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212. © 2014, The American College of Clinical Pharmacology.

  17. Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor▿

    PubMed Central

    Jordan, Robert; Tien, Deborah; Bolken, Tove' C.; Jones, Kevin F.; Tyavanagimatt, Shanthakumar R.; Strasser, Josef; Frimm, Annie; Corrado, Michael L.; Strome, Phoebe G.; Hruby, Dennis E.

    2008-01-01

    ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection. PMID:18316519

  18. Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor.

    PubMed

    Jordan, Robert; Tien, Deborah; Bolken, Tove' C; Jones, Kevin F; Tyavanagimatt, Shanthakumar R; Strasser, Josef; Frimm, Annie; Corrado, Michael L; Strome, Phoebe G; Hruby, Dennis E

    2008-05-01

    ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection.

  19. Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects

    PubMed Central

    Kim, Choon Ok; Oh, Eun Sil; Choi, Chungam; Kim, Yeonjoo; Lee, Sera; Kim, Semi; Park, Min Soo

    2016-01-01

    CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (Cmax) at 5–6 h post-dose, and had a long terminal half-life ranging between 40–70 h. The area under the plasma concentration–time curve (AUC) and Cmax increased with the dose, however, Cmax and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%–83%) was observed at 6–8 h post-dose. A sigmoid Emax model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC50 of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity. PMID:27895466

  20. Alfuzosin: overview of pharmacokinetics, safety, and efficacy of a clinically uroselective alpha-blocker.

    PubMed

    Roehrborn, C G

    2001-12-01

    Efficacy and safety of alfuzosin administered as 3-times-daily and 2-times-daily formulations have been previously demonstrated in placebo-controlled studies, and these formulations have been commercially available in many countries. A once-daily formulation of alfuzosin administered through a novel prolonged-release system has been recently developed to improve the convenience of dosing and to provide optimal pharmacokinetic coverage over 24 hours. The results of 2 double-blind, placebo-controlled phase 3 studies in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia suggests that 10 mg of alfuzosin administered once daily without dose titration is superior to placebo in terms of symptom and urinary flow rate improvement. Orthostatic hypotension and first-dose phenomenon related to the alpha-blocking property were rare. The incidences of asthenia and fatigue were comparable to those seen with placebo. Ejaculatory disorders were very rare. The most frequently reported adverse event potentially related to alpha blockade was dizziness, which occurred in 5.0% of patients treated with 10 mg alfuzosin compared with 2.1% of patients given placebo.

  1. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability.

    PubMed

    Citrome, Leslie

    2013-02-01

    Cariprazine is an atypical antipsychotic in clinical development for the treatment of schizophrenia and bipolar mania/mixed episodes. The purpose of this review is to describe the chemistry, pharmacodynamic profile, pharmacokinetics, and clinical profile of cariprazine. Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist. Doses ≥ 1.5 mg/d yielded 69 - 75% D2/D3 receptor occupancy as measured in positron emission tomography scans. Mean half-life for cariprazine was 2 - 5 d over a dose range of 1.5 - 12.5 mg. Cariprazine produces two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine, the latter having a longer half-life than cariprazine. Exposure to didesmethyl-cariprazine exceeded that of the parent drug. Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6. The efficacy and safety of cariprazine have been so far investigated only in a few short-term (unpublished) clinical trials; however, three studies in schizophrenia and three studies in bipolar mania/mixed episodes evidenced a statistically significant therapeutic effect compared to placebo for cariprazine at doses ranging from 1.5 to 12 mg/d. There does not appear to be clinically relevant adverse effects of cariprazine on metabolic variables. Commonly encountered adverse events associated with cariprazine include insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness, and constipation.

  2. Efficacy, safety and pharmacokinetics of a novel subcutaneous immunoglobulin, Evogam®, in primary immunodeficiency.

    PubMed

    Empson, Marianne B; Tang, Mimi L K; Pearce, Lisa K C; Rozen, Leon; Gold, Michael S; Katelaris, Constance H; Langton, David; Smart, Joanne; Smith, William B; Steele, Richard H; Ziegler, John B; Maher, Darryl

    2012-10-01

    This phase III, open-label, multi-centre study investigated the efficacy, safety, pharmacokinetics and quality of life impact of Evogam(®), a new chromatographically fractionated 16% subcutaneous immunoglobulin, utilising a 1:1 dose transition ratio from previous immunoglobulin therapy. Thirty-five previously treated patients with primary immunodeficiency received weekly Evogam over 36 weeks. Primary endpoints were rate of serious bacterial infections (SBIs) and steady-state serum immunoglobulin G (IgG) trough concentrations. No SBIs were reported during the study. Evogam produced significantly higher mean trough IgG concentrations with 1:1 dose conversion compared to previous immunoglobulin treatment (8.94 versus 8.27 g/L, p = 0.0063). Evogam was efficacious in the prevention of infections and maintenance of trough levels using a 1:1 dose conversion. It was well tolerated with no withdrawals due to adverse events and was preferred to IVIg by the majority of patients.

  3. Pharmacokinetics, safety, and tolerability of faldaprevir in patients with renal impairment.

    PubMed

    Huang, Fenglei; Moschetti, Viktoria; Lang, Benjamin; Halabi, Atef; Petersen-Sylla, Marc; Yong, Chan-Loi; Elgadi, Mabrouk

    2015-01-01

    Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.).

  4. Pharmacokinetics and safety of olopatadine hydrochloride 0.77% in healthy subjects with asymptomatic eyes: data from 2 independent clinical studies

    PubMed Central

    Meier, Edward; Narvekar, Abhijit; Iyer, Ganesh R; DuBiner, Harvey B; Vutikullird, Apinya; Wirta, David; Sall, Kenneth

    2017-01-01

    Purpose To assess the pharmacokinetics and safety of hydrochloride ophthalmic solution 0.77% olopatadine from 2 independent (Phase I and Phase III, respectively) clinical studies in healthy subjects. Materials and methods The Phase I, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥18 years old (N=36) to assess the systemic pharmacokinetics of olopatadine 0.77% following single- and multiple-dose exposures. The Phase III, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥2 years old (N=499) to evaluate long-term ocular safety of olopatadine 0.77%. Subjects received olopatadine 0.77% or vehicle once daily bilaterally for 7 days in the pharmacokinetic study and 6 weeks in the safety study. Results In the pharmacokinetic study, olopatadine 0.77% was absorbed slowly and reached a peak plasma concentration (Cmax) of 1.65 ng/mL following single-dose and 1.45 ng/mL following multiple-dose exposures in 2 hours (time to reach maximum plasma concentration [Tmax]). After reaching peak concentrations, olopatadine showed a similar mono-exponential decay following single and multiple doses with mean elimination half-life ranging from 2.90 to 3.40 hours. No accumulation in olopatadine exposure (Cmax and area under the plasma concentration–time curve from 0 to 12 hours) was evident after multiple doses when compared to single dose. In the safety study, treatment-emergent adverse events were reported in 26.7% and 31.4% of subjects with olopatadine 0.77% and vehicle, respectively. Blurred vision was the most frequent ocular treatment-emergent adverse event in both treatment groups (olopatadine 0.77% vs vehicle, 4.8% vs 4.1%). No deaths or serious adverse events were reported during the study. Conclusion Olopatadine 0.77% had minimal systemic exposure or accumulation in healthy subjects and was well tolerated in both adult and pediatric subjects. PMID:28435218

  5. Investigation of the safety of topical metronidazole from a pharmacokinetic perspective.

    PubMed

    Iida, Junichi; Kudo, Toshiyuki; Shimada, Kento; Yatsuno, Yoshiyuki; Yamagishi, Saori; Hasegawa, Satoshi; Ike, Hideyuki; Sato, Toru; Kagaya, Hajime; Ito, Kiyomi

    2013-01-01

    Metronidazole (MTZ) ointment has been used widely as a hospital preparation against cancerous malodor. Although cancerous tissue with ulcer-like symptoms is likely to have a higher capacity to absorb drugs than normal skin, the extent to which MTZ is absorbed when a topical preparation is applied to cancerous tissue remains unclear. Furthermore, few studies have investigated the drug interactions involving MTZ despite its long use in clinical practice. In the present study, plasma concentration of MTZ was measured in a breast cancer patient using MTZ ointment for cancerous malodor and basic research was also conducted with the objective of investigating the safety of topical MTZ from a pharmacokinetic perspective. 4.75 µg/mL (27.8 µM) of MTZ was detected in the patient's plasma, which was close to the plasma concentration after oral dosage of MTZ. In a metabolic inhibition study using human liver microsomes, cytochrome P450 (CYP) 2C9-mediated hydroxylation of S-warfarin was almost unaffected by MTZ at the corresponding concentrations. In addition, 3-d repeated oral administration of MTZ (200 mg/kg/d) to rats did not show any significant effects on the hepatic mRNA levels of various CYP isozymes and CYP2C protein levels. These results suggest that the reported interaction of oral MTZ and S-warfarin was not due to CYP2C9 inhibition and that drug interactions via inhibition of CYP2C9 is unlikely to occur when MTZ ointment is applied to ulcerous skin. This information should be valuable for assessing the safety of MTZ ointment used for mitigating cancerous malodor.

  6. Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis.

    PubMed

    Thomsen, Edward K; Sanuku, Nelly; Baea, Manasseh; Satofan, Samson; Maki, Elit; Lombore, Bart; Schmidt, Mark S; Siba, Peter M; Weil, Gary J; Kazura, James W; Fleckenstein, Lawrence L; King, Christopher L

    2016-02-01

    Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown. We performed a pilot study to test the efficacy, safety, and pharmacokinetics of single-dose DEC, IVM, and ALB in Wuchereria bancrofti-infected Papua New Guineans. Adults were randomized into 2 treatment arms, DEC 6 mg/kg + ALB 400 mg (N = 12) or DEC 6 mg/kg + ALB 400 mg + IVM 200 μg/kg (N = 12), and monitored for microfilaria, parasite antigenemia, adverse events (AEs), and serum drug levels. Triple-drug therapy induced >2-log reductions in microfilaria levels at 36 and 168 hours after treatment compared with approximately 1-log reduction with 2 drugs. All 12 individuals who received 3 drugs were microfilaria negative 1 year after treatment, whereas 11 of 12 individuals in the 2-drug regimen were microfilaria positive. In 6 participants followed 2 years after treatment, those who received 3 drugs remained microfilaria negative. AEs, particularly fever, myalgias, pruritus, and proteinuria/hematuria, occurred in 83% vs 50% of those receiving triple-drug compared to 2-drug treatment respectively (P = .021); all resolved within 7 days after treatment. No serious AEs were observed in either group. There was no significant effect of IVM on DEC or ALB drug levels. Triple-drug therapy is safe and more effective than DEC + ALB for Bancroftian filariasis and has the potential to accelerate elimination of lymphatic filariasis. NCT01975441. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  7. Safety and Pharmacokinetics of CD101 IV, a Novel Echinocandin, in Healthy Adults

    PubMed Central

    Ong, Voon; Lee, Jonathan; Thye, Dirk

    2016-01-01

    ABSTRACT CD101 IV is a novel echinocandin with distinctive pharmacokinetic properties that is being developed as a once-weekly treatment for candidemia and invasive candidiasis. CD101 has potent in vitro activity and in vivo efficacy against a broad range of Candida and Aspergillus species. The primary objective of two randomized, double-blind, placebo-controlled, dose-escalation studies in healthy adults was to determine the safety and tolerability of CD101 IV. Sequential cohorts of 8 subjects (n = 6, active; n = 2, placebo) were administered single (50, 100, 200, 400 mg) or multiple once-weekly (100 mg given once weekly for two weeks [×2], 200 mg ×2, 400 mg ×3) doses of CD101 IV infused over 1 h. There were no deaths, serious adverse events (SAEs), severe adverse events (AEs), or withdrawals from the study due to an AE. The majority of AEs were mild, and all completely resolved. There was a higher incidence of total AEs and mild transient infusion reactions in the 400-mg ×3 dose group. There were no clinically meaningful trends in postbaseline laboratory abnormalities and no safety issues related to electrocardiograms, vital signs, or physical exams. CD101 showed dose-proportional plasma exposures, minor accumulation (30% to 55%), low apparent clearance (<0.28 liter/h), long half-life (t1/2) (>80 h), and minimal urine excretion. CD101 IV was safe and well tolerated at single and multiple doses of up to 400 mg given once weekly for 3 weeks and exhibited a long t1/2, minimal accumulation over several weeks, negligible renal excretion, and high plasma exposures enabling once-weekly dosing. PMID:27919901

  8. Evaluation of Pharmacokinetic Assumptions Using a 443 Chemical Library (SOT)

    EPA Science Inventory

    With the increasing availability of high-throughput and in vitro data for untested chemicals, there is a need for pharmacokinetic (PK) models for in vitro to in vivo extrapolation (IVIVE). Though some PBPK models have been created for individual compounds using in vivo data, we ...

  9. Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients.

    PubMed

    Collins, P W; Quon, D V K; Makris, M; Chowdary, P; Kempton, C L; Apte, S J; Ramanan, M V; Hay, C R M; Drobic, B; Hua, Y; Babinchak, T J; Gomperts, E D

    2017-08-17

    Trenonacog alfa (IB1001) is a recombinant factor IX (rFIX) manufactured in Chinese hamster ovary (CHO) cells. IB1001 was evaluated in a multicentre clinical trial with haemophilia B patients. The aim was to establish IB1001 pharmacokinetic non-inferiority to comparator rFIX, safety and efficacy in previously treated patients (PTPs) with haemophilia B. Subjects were severe or moderately severe haemophilia B adult and adolescent PTPs with no history of FIX inhibitors. IB1001 PK non-inferiority to comparator rFIX was demonstrated through ratio of AUC0-∞ in 32 subjects. IB1001 was well tolerated in all 76 treated subjects; the most common adverse drug reaction was headache (2.6% of subjects) and there were no reports of FIX inhibitors. Transient non-inhibitory binding FIX antibodies and anti-CHO cell protein antibodies developed in 21% and 29% of subjects respectively; no safety concerns were associated with development of these antibodies. Prophylaxis (mean duration ± SD: 17.9 ± 9.6 months, mean dose: 55.5 ± 12.9 IU/kg, median 1.0 infusion per week) was effective in preventing bleeds (median annual bleed rate: 1.52, interquartile range: 0.0-3.46). One or two IB1001 infusions resolved 84% of the bleeds, while for 84% of treatments haemostatic efficacy of IB1001 was rated excellent or good. IB1001 haemostatic efficacy for all 19 major surgeries was rated adequate or better than adequate. IB1001 is safe and efficacious for treatment of bleeds, routine prophylaxis and perioperative management in haemophilia B patients. © 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

  10. The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMV-seropositive patients

    PubMed Central

    Jung, Donald; AbdelHameed, Magdy H; Hunter, John; Teitelbaum, Philip; Dorr, Albert; Griffy, Kay

    1999-01-01

    Aims We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV-and CMV-seropositive patients. Methods In an open-label, randomized, 3-way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7-day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment. Results The presence of trimethoprim significantly decreased CLr (12.9%, P = 0.0068) and increased t1/2 (18.1%, P = 0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprim. Conclusions There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered. PMID:10215748

  11. Chitosan-Stearic Acid Based Polymeric Micelles for the Effective Delivery of Tamoxifen: Cytotoxic and Pharmacokinetic Evaluation.

    PubMed

    Thotakura, Nagarani; Dadarwal, Mukesh; Kumar, Pramod; Sharma, Gajanand; Guru, Santosh Kumar; Bhushan, Shashi; Raza, Kaisar; Katare, Om Prakash

    2017-04-01

    Chitosan is a widely employed polysaccharide with positive zeta-potential and better tissue/cell adhesion. Its hydrophilicity, high viscosity, and insolubility at physiological pH are major hurdles in proper utilization of this macromolecule. Therefore, it was conjugated with biocompatible stearic acid and the conjugate was employed to develop polymeric micelles for delivery of tamoxifen to breast cancer cells. The conjugate was characterized by FT-IR and NMR, and the nanocarrier was characterized for micromeritics, surface charge, drug loading, and morphological attributes. The efficacy was evaluated by in vitro MTT studies, safety by erythrocyte compatibility, and biodistribution by in vivo pharmacokinetic studies. Despite better drug loading and sustained drug release, cytotoxicity on MCF-7 breast cancer cells was substantially enhanced and the pharmacokinetic profile was significantly modified. The AUC was enhanced manifolds along with reduced clearance. The findings are unique and provide an alternative to the conventional lipid-based nanocarriers for better dose delivery, tissue adhesion, and desired pharmacokinetic modulation.

  12. Pharmacokinetics and safety of ceftiofur crystalline free acid in New Zealand White rabbits (Oryctolagus cuniculus).

    PubMed

    Gardhouse, Sara; Guzman, David Sanchez-Migallon; Cox, Sherry; Kass, Philip H; Drazenovich, Tracy L; Byrne, Barbara A; Hawkins, Michelle G

    2017-07-01

    OBJECTIVE To determine the pharmacokinetics and adverse effects following SC administration of ceftiofur crystalline free acid (CCFA) in New Zealand White rabbits. ANIMALS 6 adult sexually intact female New Zealand White rabbits. PROCEDURES Each rabbit was administered 40 mg of CCFA/kg SC. A blood sample was obtained immediately before (0 minutes), at 5 and 30 minutes after, and at 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 95, 120, 144, and 168 hours after administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured. Pharmacokinetic parameters were calculated. For each rabbit, body weight, food consumption, fecal output, and injection site were monitored. Minimum inhibitory concentrations of ceftiofur for 293 bacterial isolates from rabbit clinical samples were determined. RESULTS Mean ± SD peak plasma concentration of CFAE and time to maximum plasma concentration were 33.13 ± 10.15 μg/mL and 1.75 ± 0.42 hours, respectively. The mean terminal half-life of CFAE was 42.6 ± 5.2 hours. Plasma CFAE concentration was > 4 μg/mL for approximately 24 hours and > 1 μg/mL for at least 72 hours after CCFA administration. An apparently nonpainful subcutaneous nodule developed at the injection site in 3 of 6 rabbits. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that CCFA (40 mg/kg) could be administered SC every 24 to 72 hours to New Zealand White rabbits to treat infections with ceftiofur-susceptible bacteria. Single-dose administration of CCFA resulted in minimal adverse effects. Additional studies are needed to evaluate the effects of repeated CCFA administration in New Zealand White rabbits.

  13. Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study.

    PubMed

    Syn, Nicholas Li-Xun; Wang, Lingzhi; Wong, Andrea Li-Ann; Soe, Mu-Yar; Chuah, Benjamin; Chan, Daniel; Tan, Sing-Huang; Soo, Ross Andrew; Lee, Soo-Chin; Goh, Boon-Cher; Yong, Wei-Peng

    2016-02-01

    Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We carried out the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1, normal; Category 2, mild--alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase ≤5× upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate--any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5-10× ULN, and/or total bilirubin ≤1-1.5× ULN. Category 1, 2 and 3 patients received starting dosages of 40, 30, and 20 mg/m(2) docetaxel, respectively. Pharmacokinetics were evaluated on day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was carried out weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P < 0.001). Median clearance was 22.8, 16.4, and 11.3 L/h/m(2) in Categories 1, 2, and 3, respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (area under the concentration-time curve) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median area under the concentration-time curve was 1.74, 1.83, and 1.77 mg·h/L in Categories 1, 2, and 3, respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group grouping systems suggests that the proposed

  14. Preclinical Studies on the Pharmacokinetics, Safety and Toxicology of Oxfendazole: Toward First in Human Studies

    PubMed Central

    Codd, Ellen E.; Ng, Hanna H.; McFarlane, Claire; Riccio, Edward S.; Doppalapudi, Rupa; Mirsalis, Jon C.; Horton, R. John; Gonzalez, Armando E.; Garcia, H. Hugo; Gilman, Robert H.

    2015-01-01

    A two-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased WBC levels, a class effect of benzimidazole anthelminthics, returned to normal during the recovery period. The NOAEL was determined to be >5 but < 25 mg/kg/d and the MTD 100 mg/kg/d. The highest dose, 200 mg/kg/d resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after seven days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma or rat micronucleus assays, nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases. PMID:25701764

  15. 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

  16. 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.

  17. A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

    PubMed

    Gutman, Dikla; Hellriegel, Edward; Aycardi, Ernesto; Bigal, Marcelo E; Kunta, Jeevan; Chitra, Rohini; Kansagra, Sujay; Kidron, Orna Srur; Knebel, Helena; Linder, Steven; Ma, Yuju; Pierce, Mark; Winner, Paul K; Spiegelstein, Ofer

    2016-09-01

    To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger

  18. Safety and Pharmacokinetics of Once-Daily Dapsone Gel, 7.5% in Patients With Moderate Acne Vulgaris.

    PubMed

    Jarratt, Michael T; Jones, Terry M; Chang-Lin, Joan-En; Tong, Warren; Berk, David R; Lin, Vince; Kaoukhov, Alexandre

    2016-10-01

    Reducing the dosing frequency of topical acne treatments to once daily may improve adherence. Evaluate pharmacokinetics (PK), safety, and tolerability of 3 formulations of once-daily dapsone gel, 7.5% and of twice-daily dapsone gel, 5% over 28 days in patients with moderate acne vulgaris. This phase 1, multicenter, parallel-group study randomized males and females aged 16 to 35 years to 1 of 3 dapsone gel, 7.5% formulations (DAP-11078, DAP-11079, or DAP-11080 double-blind; applied once daily) or to dapsone gel, 5% (investigator-blinded only, applied twice-daily). Blood samples were collected for PK assessments of dapsone and its metabolites, N-acetyl dapsone (NAD) and dapsone hydroxylamine (DHA), before the morning dose on days 1, 7, 14, 18, 21, 26, 27, and 28, and at several follow-up time points (days 29-32). Safety profile assessments included adverse events (AEs), physical examinations, laboratory tests, and local tolerability assessments. Steady-state dapsone, NAD, and DHA concentrations were reached within 7 days of the first dose in all treatment groups. Daily systemic exposures of the 3 dapsone gel, 7.5% formulations were approximately 25% to 40% lower than that for dapsone gel, 5%, and these differences were statistically significant. Among the 3 dapsone gel, 7.5% formulations, the highest daily exposure of dapsone (per the AUC) was observed with DAP-11080, with respective Cmax and AUC0-24 being approximately 28.6% and 28.7% lower relative to dapsone gel, 5%. Most AEs were mild to moderate in intensity. The safety profiles for all 3 formulations of once-daily dapsone, 7.5% gel and twice-daily dapsone gel, 5% were similar following 28 days of topical administration. All 4 dapsone formulations were well tolerated. This study demonstrated lower systemic exposure with all 3 once-daily dapsone gel, 7.5% formulations than with twice-daily dapsone gel, 5%. All 4 formulations were well tolerated and demonstrated similar safety profiles.

    J Drugs

  19. Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: a phase 1, randomized controlled study.

    PubMed

    Mann, Donald; Liu, Jing; Chew, Marci L; Bockbrader, Howard; Alvey, Christine W; Zegarac, Elizabeth; Pellock, John; Pitman, Verne W

    2014-12-01

    To evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures. This was a phase 1, randomized, placebo-controlled, parallel-group, escalating-dose, multiple-dose study comprising a 7-day, double-blind treatment period and a single-blind, single dose of pregabalin administered to all children on day 8. Children in four age cohorts (1-23 months, 2-6, 7-11, and 12-16 years) received one of four doses of pregabalin (2.5, 5, 10, or 15 mg/kg/day) or placebo. Safety and tolerability were assessed throughout the study. Steady-state and single-dose PK parameters on day 8 were analyzed using standard noncompartmental procedures. Sixty-five children received at least one dose of treatment. Four pregabalin-treated children discontinued treatment, three of whom received 15 mg/kg/day. Two children experienced serious adverse events, one of whom received pregabalin 15 mg/kg/day. During double-blind treatment, the most common adverse events reported in the pregabalin-treated population were somnolence (27.1%) and dizziness (12.5%). Steady-state pregabalin peak and total exposure in each age cohort appeared to increase linearly with dose. Apparent oral clearance (CL/F) was directly related to creatinine clearance, consistent with adults. CL/F normalized for body weight was 43% higher in patients weighing <30 kg. Steady-state and single-dose PK were consistent. Pregabalin at doses up to 10 mg/kg/day in children aged 1 month to 16 years, and at doses up to 15 mg/kg/day in those aged <6 years, demonstrated acceptable safety and tolerability. For children weighing <30 kg, a dose increase of 40% (mg/kg dosing) is required to achieve comparable exposure with adults or children weighing ≥30 kg. These data will inform dose selection in phase 3 trials of the efficacy and safety of adjunctive pregabalin in children with refractory partial seizures. Wiley Periodicals, Inc. © 2014 International League Against

  20. Drug safety evaluation of defibrotide.

    PubMed

    Richardson, Paul G; Corbacioglu, Selim; Ho, Vincent Trien-Vinh; Kernan, Nancy A; Lehmann, Leslie; Maguire, Craig; Maglio, Michelle; Hoyle, Margaret; Sardella, Marco; Giralt, Sergio; Holler, Ernst; Carreras, Enric; Niederwieser, Dietger; Soiffer, Robert

    2013-01-01

    Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). Defibrotide (DF) has been shown in Phase II and III trials to improve complete response in patients with severe VOD (sVOD). None of the articles, to date, provide a comprehensive review of the safety of DF in VOD and/or a range of other conditions. This article reviews current clinical findings on DF, primarily in terms of safety for use in treatment and prophylaxis of VOD, and relevant safety data for its use in other diseases. The literature review was conducted using a PubMed search with the fixed term 'defibrotide' in combination with ≥ 1 of 'safety', 'veno-occlusive disease' (with and without 'treatment', 'prevention'), 'oncology', 'myeloma', 'microangiopathy', 'anti-thrombotic' and 'peripheral vascular disorder'. Related articles from the EBMT and ASH conference websites were also included. DF was well tolerated in majority of the studies. The safety profile of DF is largely favourable with toxicities comparable to control populations in the setting of SCT complicated by sVOD.

  1. A Pharmacokinetic and Safety Study of Trebananib, a Fc-Fusion Peptibody, in Patients with Advanced Solid Tumors and Varying Degrees of Renal Dysfunction.

    PubMed

    Wu, Benjamin; Lewis, Lionel D; Harvey, R Donald; Rasmussen, Erik; Gamelin, Erick; Sun, Yu-Nien; Friberg, Gregory; Koyner, Jay L; Dowlati, Afshin; Maitland, Michael L

    2017-01-11

    Clearance of trebananib (AMG 386), a 64 kD anti-angiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg IV weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments. For 28 patients, trebananib clearance decreased from normal renal function (1.52 mL/hr/kg), to mild (1.20 mL/hr/kg), moderate (0.79 mL/hr/kg), and severe (0.53 mL/hr/kg) renal dysfunction (P ≤ 0.001). Treatment-related adverse events showed no association with clearance. Trebananib clearance was proportional to eGFR and unrelated to pretreatment protein excretion. These data confirm a role for renal clearance of a recombinant peptibody with molecular weight < 69 kD and support a longer dosing interval for patients with severe renal dysfunction. This article is protected by copyright. All rights reserved.

  2. [Clinical and pharmacokinetic evaluation of ceftriaxone in children].

    PubMed

    Fujita, K; Sakata, H; Murono, K; Yoshioka, H; Maruyama, S; Sanae, N

    1984-12-01

    Twenty-eight pediatric patients were treated with ceftriaxone (Ro 13-9904, CTRX) in the doses ranging from 8.75 to 25 mg/kg every 12 hours for 3.5 to 11.5 days, and the clinical efficacy and side effects were evaluated. Among the 21 children with bacterial infections including pneumonia, acute bronchitis, otitis media, tonsillitis and urinary tract infections, the results were excellent in 9, good in 11, and fair in 1 patient. Out of the 28 patients, 2 patients had diarrhea, 3 patients had slightly elevated serum concentrations of transaminases, and 2 patients showed eosinophilia. The serum concentrations of CTRX in 5 children ranged from 50.0 to 93.8 micrograms/ml (mean 75.0 micrograms/ml) at 15 minutes and from 10.2 to 15.6 micrograms/ml (mean 13.4 micrograms/ml at 6 hours after 10 mg/kg intravenous bolus injection of CTRX. The serum half-lives were from 2.61 to 8.30 hours (mean 6.16 hours), and urinary recovery rates were from 43.3 to 58.0% (mean 48.5%) during 0-6 hours and from 52.0 to 66.1% (mean 59.4%) during 0-12 hours. After 20 mg/kg intravenous bolus injection of CTRX in 4 children, the serum concentrations of CTRX were from 118.8 to 162.5 micrograms/ml (mean 139.1 micrograms/ml) at 15 minutes and from 18.0 to 21.1 micrograms/ml (mean 19.2 micrograms/ml) at 6 hours. The serum half-lives were 4.07 to 6.34 hours (mean 5.13 hours), and urinary recovery rates were 38.6 to 51.1% (mean 45.4%) during 0-6 hours and from 54.8 to 64.0% (mean 59.0%) during 0-12 hours. Patients with impairment of renal function were excluded from this pharmacokinetic study.

  3. Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two Phase II trials.

    PubMed

    Gabrail, Nashat; Yanagihara, Ronald; Spaczyński, Marek; Cooper, William; O'Boyle, Erin; Smith, Carrie; Boccia, Ralph

    2015-01-01

    Despite advances with new therapies, a significant proportion of patients (>30%) suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively) in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy. In C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated. APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema and induration) were predominantly mild and seen in ≤20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in ≥80% and ≥75% of patients in both trials with the 250 and 500 mg doses, respectively. After a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and maintained therapeutic granisetron

  4. Safety and pharmacokinetics of hyperimmune anti-human immunodeficiency virus (HIV) immunoglobulin administered to HIV-infected pregnant women and their newborns. Pediatric AIDS Clinical Trials Group Protocol 185 Pharmacokinetic Study Group.

    PubMed

    Lambert, J S; Mofenson, L M; Fletcher, C V; Moye, J; Stiehm, E R; Meyer, W A; Nemo, G J; Mathieson, B J; Hirsch, G; Sapan, C V; Cummins, L M; Jimenez, E; O'Neill, E; Kovacs, A; Stek, A

    1997-02-01

    The pharmacokinetics and safety of hyperimmune anti-human immunodeficiency virus (HIV) intravenous immunoglobulin (HIVIG) were evaluated in the first 28 maternal-infant pairs enrolled in a randomized, intravenous immunoglobulin (IVIG)-controlled trial of HIVIG maternal-infant HIV transmission prophylaxis. Using 200 mg/kg, mean half-life and volume of distribution (Vd) in women were 15 days and 72 mL/kg, respectively, after one and 32 days and 154 mL/kg after three monthly infusions, with stable 4 mL/kg/day clearance. Transplacental passage occurred. Newborn single-dose half-life, Vd, and clearance were 30 days, 143 mL/kg, and 4 mL/kg/day, respectively. HIVIG rapidly cleared maternal serum immune complex-dissociated p24 antigen, and plasma HIV-1 RNA levels were stable. Mild to moderate adverse clinical effects occurred in 2 of 103 maternal and 2 of 25 infant infusions. No adverse hematologic, blood chemistry, or immunologic effects were seen. HIVIG is well-tolerated in HIV-infected pregnant women and their newborns, clears antigenemia, crosses the placenta, and exhibits pharmacokinetics similar to those of other immunoglobulin preparations.

  5. Evaluation of the Safety and Efficacy of the FAAH Inhibitor URB597

    DTIC Science & Technology

    2016-01-01

    nyumc.org! ! ! 5f.2WORK2UNIT2NUMBER 7.2PERFORMING2ORGANIZATION2NAME(S)2AND2ADDRESS(ES)2 New York University 550 First Avenue & One Park Avenue, Room 8...formulations,!and!(3)!evaluation!of!the!safety/toxicology!of!the! drug!substance!in!preclinical!models!including! rat !and!nonAhuman!primates,!and! (4...pharmacokinetics!of!the!drug!formulations,!and!(3)!evaluation!of!the!safety/toxicology!of!the! drug!substance!in!preclinical!models!including! rat

  6. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban--an oral, direct factor Xa inhibitor--are not affected by aspirin.

    PubMed

    Kubitza, Dagmar; Becka, Michael; Mueck, Wolfgang; Zuehlsdorf, Michael

    2006-09-01

    Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This was a randomized, 2-way crossover study in healthy male subjects, with an aspirin run-in period, to examine whether aspirin influences the safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban. All treatments were well tolerated; drug-related adverse events were mild and transient. Aspirin did not alter the effects of rivaroxaban on Factor Xa activity or clotting tests. Platelet aggregation and bleeding time were not affected by rivaroxaban, and rivaroxaban did not influence the effects of aspirin on these parameters to a clinically relevant extent. Aspirin did not affect the pharmacokinetics of rivaroxaban, including the fraction unbound. This study suggests that there is no clinically relevant interaction between rivaroxaban and aspirin and that the 2 drugs could be administered concomitantly at the doses used in this study.

  7. Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users.

    PubMed

    Harris, Stephen C; Perrino, Peter J; Smith, Ira; Shram, Megan J; Colucci, Salvatore V; Bartlett, Cynthia; Sellers, Edward M

    2014-04-01

    The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled-release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double-blind, positive- and placebo-controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg). Pharmacokinetics, pharmacodynamics (e.g., Overall Drug Liking [ODL], Take Drug Again [TDA], and High Visual Analog Scales [VAS]; Subjective Drug Value [SDV]; pupillometry; intranasal irritation), and safety (e.g., adverse events, vital signs, laboratory tests) were assessed to 24 hours postdose. Crushed ORF administration yielded reduced oxycodone Cmax and increased Tmax versus crushed OC and Oxy API. Peak effects for pharmacodynamic measures were delayed with ORF (1-2 hours) versus OC and Oxy API (0.5-1 hour). ODL, TDA, High VAS, and SDV Emax values were significantly lower (P ≤ .05) and some intranasal irritation ratings were greater for ORF versus OC and Oxy API. No significant or unexpected safety findings were observed. Compared with OC and Oxy API, intranasally administered ORF was associated with lower and delayed peak plasma concentrations, decreased drug-liking, and decreased intranasal tolerability. This suggests that ORF has a decreased potential for intranasal oxycodone abuse. There were no significant or unexpected safety findings. As is true for all abuse potential studies, epidemiological or other appropriate post-marketing studies are required to assess the impact of the reduction in intranasal oxycodone abuse potential observed in the present study on real-world patterns of ORF misuse, abuse, and diversion.

  8. 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

  9. Ocular Safety and Pharmacokinetics Study of FK506 Suspension Eye Drops After Corneal Transplantation

    PubMed Central

    Yuan, Jin; Zhai, Jia-jie; Huang, Xi; Zhou, Shi-you

    2012-01-01

    Abstract Purpose The aim of this study was to investigate the sensitization, pharmacokinetics, and absorption of FK506 after corneal transplantation. Methods New Zealand albino rabbits were divided into normal and corneal transplantation groups. Each group was divided into 5 subgroups—saline, blank matrix, high-dose, medium-dose, and low-dose, respectively. There were 10 rabbits in each subgroup. One drop (25 μL) of FK506 was administered topically to both eyes of the rabbits 4 times daily for 30 days. Thirty days later, 5 rabbits of each subgroup were sacrificed after the administration of the last dose. Both eyes were enucleated; the left eye was used for pathologic examination and the right eye for the determination of FK506 distribution. The other 5 rabbits in each subgroup were sacrificed 14 days after the former 5 rabbits were sacrificed, and their eyes were enucleated for pathologic examination and tissue distribution determination as the former 5 rabbits in each subgroup (the second batch). Results Fluorescein staining and local ocular reaction provided evidence that there were no significant differences between control and FK506-instilled eyes in the rabbit model at any of the tested doses. Histologic examination revealed no ocular abnormality in the rabbits instilled with any doses of FK506 eyedrop. The peak serum concentration (Cmax) of systemic absorption ranged from 4.31±0.79 ng/mL to 14.89±6.85 ng/mL. Conclusion Our study suggests that up to 0.1% FK506 administered 4 times a day (q.i.d.) topically is safe for the rabbit eye. However, further safety studies are required in view of systemic adverse effects. PMID:22136074

  10. Pharmacokinetic, partial pharmacodynamic and initial safety analysis of (−)-Epicatechin in healthy volunteers

    PubMed Central

    Barnett, Christopher F.; Moreno-Ulloa, Aldo; Shiva, Sruti; Ramirez-Sanchez, Israel; Taub, Pam R.; Su, Yongxuan; Ceballos, Guillermo; Dugar, Sundeep; Schreiner, George; Villarreal, Francisco

    2015-01-01

    (−)-Epicatechin ((−)-EPI), a naturally occurring flavanol has emerged as a likely candidate for cocoa-based product reported reductions in cardiometabolic risk. The present study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of purified (−)-EPI administered to healthy volunteers. In this phase I, open-label, two-part single- and multiple-dose study subjects received either a single dose (n=9) of 50, 100 or 200 mg or multiple doses (n=8) of 50 mg daily (q.d.) or twice daily (b.i.d) for 5 days. Blood was collected at 0, 0.5, 1, 2, 4 and 6 hrs after (−)-EPI administration in the single and multiple dose groups (blood collection repeated in day 5). Samples were analyzed by HPLC-HR-ESI-MS for EPI and metabolites quantification. In the q.d. and b.i.d. groups, blood samples were analyzed for NO surrogates, follistatin, platelet mitochondrial complex I, V and citrate synthase level determinations. (−)-EPI was well tolerated and readily absorbed with further phase 2 metabolism. On day 5, in the q.d. and b.i.d. groups, there were significant increases in plasma nitrite of 30 % and 17 %, respectively. In the q.d. group on day 5 vs. day 1, platelet mitochondria complexes I, IV and citrate synthase activities demonstrated a significant increase of ~ 92, 62 and 8 %, respectively. Average day 5 follistatin AUC levels were ~2.5 fold higher vs. day 1 AUC levels in the b.i.d. group. (−)-EPI was safe with no observed adverse effects and our findings suggest that increases in NO metabolites, mitochondrial enzyme function and plasma follistatin levels may underlie some of the beneficial effects of cocoa products or (−)-EPI as reported in other studies. PMID:25598082

  11. Pharmacokinetics, efficacy, and safety of caspofungin in Japanese pediatric patients with invasive candidiasis and invasive aspergillosis.

    PubMed

    Mori, Masaaki; Imaizumi, Masue; Ishiwada, Naruhiko; Kaneko, Takashi; Goto, Hiroaki; Kato, Koji; Hara, Junichi; Kosaka, Yoshiyuki; Koike, Kazutoshi; Kawamoto, Hiroshi; Maeda, Naoko; Yoshinari, Tomoko; Kishino, Hiroyuki; Takahashi, Kenichi; Kawahara, Shizuko; Kartsonis, Nicholas A; Komada, Yoshihiro

    2015-06-01

    The antifungal agents approved in Japan for pediatric use are limited and many unapproved drugs are actually used without clear instruction for dosage. We investigated the pharmacokinetics of caspofungin for the treatment of invasive candidiasis and invasive aspergillosis in 20 Japanese pediatric patients using a pediatric-specific dosage based on body surface area. Caspofungin was administered intravenously over 60 min as 70 mg/m(2) on Day 1, followed by 50 mg/m(2) per day. Five or 4 point blood sampling were done in 15 patients on Day 4-5 to calculate AUC0-24 h. The geometric means (95% confidence interval) of C24 h and AUC0-24 h in the pediatric patients were 3.3(2.5, 4.4) μg/mL and 175.1 (139.3, 220.1) μg hr/mL, respectively, which were comparable to those in Japanese adult patients [3.2 (2.8, 3.5) μg/mL and 144.9 (131.7, 159.3) μg hr/mL, respectively]. Among the 20 patients, 10 (50%) had at least 1 drug-related adverse event which was considered related to caspofungin therapy. No drug-related serious adverse event and no death occurred. The most common drug-related adverse events were events relating to hepatic function (mainly increases in ALT and AST). The overall success in efficacy was observed in 13 of 20 patients. In conclusion, once daily administration of caspofungin (70 mg/m(2) on Day 1, followed by 50 mg/m(2) [maximum daily dose not to exceed 70 mg]), which is the same dosage being used in overseas, achieved sufficient drug exposure and a favorable efficacy and acceptable safety profile in Japanese pediatric patients with invasive fungal infections.

  12. Antiparasitic drugs for paediatrics: systematic review, formulations, pharmacokinetics, safety, efficacy and implications for control.

    PubMed

    Keiser, Jennifer; Ingram, Katrin; Utzinger, Jürg

    2011-10-01

    Drug development for paediatric applications entails a number of challenges, such as the wide age spectrum covered - from birth to adolescence - and developmental changes in physiology during biological maturation that influence the efficacy and toxicity of drugs. Safe and efficacious antiparasitic drugs for children are of pivotal importance given the large proportion of burden attributable to parasitic diseases in this age group, and growing efforts to administer, as widely as possible, antiparasitic drugs to at-risk populations, such as infants and school-aged children, often without prior diagnosis. The purpose of this review is to investigate whether antiparasitic drugs have been adequately studied for use in paediatrics. We approached this issue through a systematic review using PubMed and the Cochrane Central Register of Trials covering a period of 10 years and 8 months until the end of August 2010 to identify trials that investigated efficacy, safety and pharmacokinetic (PK) parameters of antiparasitic drugs for paediatrics. Overall, 269 clinical drug trials and 17 PK studies met our inclusion criteria. Antimalarial drugs were the most commonly studied medicines (82·6%). Most trials were carried out in Africa and children aged 2-11 years were the age group most often investigated. Additionally, we critically examined available drug formulations for anthelminthics and identified a number of shortcomings that are discussed. Finally, we shed new light on current proposals to expand 'preventive chemotherapy' to preschool-aged children and emphasise that new research, including risk-benefit analyses, are needed before such a strategy can be adopted more widely.

  13. Ocular safety and pharmacokinetics study of FK506 suspension eye drops after corneal transplantation.

    PubMed

    Yuan, Jin; Zhai, Jia-jie; Huang, Xi; Zhou, Shi-you; Chen, Jia-qi

    2012-04-01

    The aim of this study was to investigate the sensitization, pharmacokinetics, and absorption of FK506 after corneal transplantation. New Zealand albino rabbits were divided into normal and corneal transplantation groups. Each group was divided into 5 subgroups--saline, blank matrix, high-dose, medium-dose, and low-dose, respectively. There were 10 rabbits in each subgroup. One drop (25 μL) of FK506 was administered topically to both eyes of the rabbits 4 times daily for 30 days. Thirty days later, 5 rabbits of each subgroup were sacrificed after the administration of the last dose. Both eyes were enucleated; the left eye was used for pathologic examination and the right eye for the determination of FK506 distribution. The other 5 rabbits in each subgroup were sacrificed 14 days after the former 5 rabbits were sacrificed, and their eyes were enucleated for pathologic examination and tissue distribution determination as the former 5 rabbits in each subgroup (the second batch). Fluorescein staining and local ocular reaction provided evidence that there were no significant differences between control and FK506-instilled eyes in the rabbit model at any of the tested doses. Histologic examination revealed no ocular abnormality in the rabbits instilled with any doses of FK506 eyedrop. The peak serum concentration (C(max)) of systemic absorption ranged from 4.31±0.79 ng/mL to 14.89±6.85 ng/mL. Our study suggests that up to 0.1% FK506 administered 4 times a day (q.i.d.) topically is safe for the rabbit eye. However, further safety studies are required in view of systemic adverse effects.

  14. 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

  15. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

    PubMed

    Stasyshyn, O; Djambas Khayat, C; Iosava, G; Ong, J; Abdul Karim, F; Fischer, K; Veldman, A; Blackman, N; St Ledger, K; Pabinger, I

    2017-04-01

    Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile.

  16. No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study

    PubMed Central

    2011-01-01

    Background Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast. Methods This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 μg tablet once daily; Day 2-18) and concomitant formoterol (24 μg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 μg twice daily; Day 2-18) and concomitant roflumilast (500 μg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study. Results Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other

  17. Switching Opioid-Dependent Patients From Methadone to Morphine: Safety, Tolerability, and Methadone Pharmacokinetics.

    PubMed

    Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Gray, Andrew; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Howes, John; Weis, Holger; Friedhoff, Lawrence

    2016-08-01

    The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60 mg/day) were switched to morphine slow-release capsules, dosed at 4× the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. Opioid withdrawal symptoms (OWS) peaked within 12-24 hours of starting morphine, and 24/27 subjects required higher daily morphine doses (mean 5.2× multiple). Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59 hours. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation, and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine. © 2016, The American College of Clinical Pharmacology.

  18. Evaluation of food safety education for consumers.

    PubMed

    Medeiros, L; Hillers, V; Kendall, P; Mason, A

    2001-01-01

    Traditionally, nutrition educators have used a fairly global approach to teach food safety by teaching a broad range of safe food handling behaviors in the expectation that this will lead to the avoidance of foodborne illness. This approach can be confusing and lead to evaluation data that are difficult to interpret. This article suggests that food safety education and evaluation in the future be organized around five behavioral constructs: practice personal hygiene, cook foods adequately, avoid cross-contamination, keep foods at safe temperatures, and avoid food from unsafe sources. These five constructs are derived from data on actual outbreaks and estimated incidences of foodborne illness. Research is needed to establish reliable and valid evaluation measures for these five behavioral constructs. Evaluation instruments can be tailored to fit specific education programs. If evaluation instruments focus on these five behavior areas, the result will be meaningful evaluation data that can be more easily summarized across food safety education programs for consumers.

  19. Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC).

    PubMed

    Meulenbeld, Hielke J; de Bono, Johann S; Tagawa, Scott T; Whang, Young E; Li, Xiaoyun; Heath, Karl H; Zandvliet, Anthe S; Ebbinghaus, Scot W; Hudes, Gary R; de Wit, Ronald

    2013-10-01

    Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug-drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer. Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide. Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration. Although there was no evidence of a clinically relevant pharmacological drug-drug interaction, the occurrence of dose-limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients.

  20. Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism.

    PubMed

    Shimatsu, Akira; Teramoto, Akira; Hizuka, Naomi; Kitai, Kazuo; Ramis, Joaquim; Chihara, Kazuo

    2013-01-01

    The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

  1. Pharmacokinetics and preliminary safety study of pod-intravaginal rings delivering antiretroviral combinations for HIV prophylaxis in a macaque model.

    PubMed

    Moss, John A; Srinivasan, Priya; Smith, Thomas J; Butkyavichene, Irina; Lopez, Gilbert; Brooks, Amanda A; Martin, Amy; Dinh, Chuong T; Smith, James M; Baum, Marc M

    2014-09-01

    Preexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 μg g(-1) (tenofovir [TFV], in vivo hydrolysis product of TDF) and 500 μg g(-1) (FTC) and in the TDF-FTC-MVC group were 10 μg g(-1) (TFV), 150 μg g(-1) (FTC), and 20 μg g(-1) (MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation.

  2. Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

    PubMed Central

    Moss, John A.; Srinivasan, Priya; Smith, Thomas J.; Butkyavichene, Irina; Lopez, Gilbert; Brooks, Amanda A.; Martin, Amy; Dinh, Chuong T.; Smith, James M.

    2014-01-01

    Preexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 μg g−1 (tenofovir [TFV], in vivo hydrolysis product of TDF) and 500 μg g−1 (FTC) and in the TDF-FTC-MVC group were 10 μg g−1 (TFV), 150 μg g−1 (FTC), and 20 μg g−1 (MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation. PMID:24936594

  3. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

    PubMed Central

    Khwaja, Omar S.; Ho, Eugenia; Barnes, Katherine V.; O’Leary, Heather M.; Pereira, Luis M.; Finkelstein, Yaron; Nelson, Charles A.; Vogel-Farley, Vanessa; DeGregorio, Geneva; Holm, Ingrid A.; Khatwa, Umakanth; Kapur, Kush; Alexander, Mark E.; Finnegan, Deirdre M.; Cantwell, Nicole G.; Walco, Alexandra C.; Rappaport, Leonard; Gregas, Matt; Fichorova, Raina N.; Shannon, Michael W.; Sur, Mriganka; Kaufmann, Walter E.

    2014-01-01

    Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities. PMID:24623853

  4. A Phase 1 Randomized Placebo-Controlled Safety and Pharmacokinetic Trial of a Tenofovir Disoproxil Fumarate Vaginal Ring

    PubMed Central

    Keller, Marla J.; Mesquita, Pedro M.; Marzinke, Mark A.; Teller, Ryan; Espinoza, Lilia; Atrio, Jessica M.; Lo, Yungtai; Frank, Bruce; Srinivasan, Sujatha; Fredricks, David N.; Rabe, Lorna; Anderson, Peter L.; Hendrix, Craig W.; Kiser, Patrick F.; Herold, Betsy C.

    2015-01-01

    Background Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), may be ideal for topical HIV preexposure prophylaxis because it has higher tissue and cell permeability than TFV, is not adversely impacted by seminal proteins, and its active metabolite, TFV-diphosphate (TFV-DP), has a long intracellular half-life. We engineered a TDF eluting polyurethane reservoir intravaginal ring (IVR) to provide near constant mucosal antiretroviral concentrations. Methods A first-in-human randomized placebo-controlled trial was conducted to assess the safety and pharmacokinetics of the TDF IVR in healthy, sexually abstinent women (15 TDF and 15 placebo). Drug concentrations were measured in cervicovaginal fluid (CVF) obtained by swab, cervical tissue, plasma, and dried blood spots (DBS) over 14 days of continuous ring use. Results There were 43 total, 23 reproductive tract, and 8 product-related Grade 1 adverse events. Steady state CVF TFV concentrations were achieved proximal (vagina, ectocervix) and distal (introitus) to the TDF IVR one day after ring insertion. Median tissue TFV-DP concentrations 14 days after TDF IVR placement were 120 fmol/mg (interquartile range 90, 550). CVF collected from the cervix one week and two weeks after TDF IVR insertion provided significant protection against ex vivo HIV challenge. Eleven of 14 (78%) participants had detectable TFV-DP DBS concentrations 14 days after TDF IVR placement, suggesting that DBS may provide a surrogate marker of adherence in future clinical trials. Conclusions A TDF IVR is safe, well tolerated, and results in mucosal TFV concentrations that exceed those associated with HIV protection. The findings support further clinical evaluation of this TDF IVR. PMID:26605514

  5. [Undesirable pharmacokinetic drug-to-drug interactions affecting the effectiveness and safety of anti-infectious pharmacotherapy].

    PubMed

    Dworacka, Marzena; Nowocień, Tamara

    2017-02-20

    The occurence of pharmacokinetic drug-to-drug interactions is the serious clinical problem in the course of pharmacotherapy of infections. Its essential part is the influence of such interactions on the effectiveness and safety of antimicrobial therapy. The aim of study was to present, the most significant on clinical hand, examples of interactions and their mechanisms between antimicrobial agents and other drugs on stages of absorption, distribution, biotransformation and elimination, leading to the decreased antimicrobial activity and ineffective pharmacotherapy or to the increased antimicrobial activity and to the increased risk of adverse effects due to agents used for anti-infectious pharmacotherapy.

  6. Prospective safety performance evaluation on construction sites.

    PubMed

    Wu, Xianguo; Liu, Qian; Zhang, Limao; Skibniewski, Miroslaw J; Wang, Yanhong

    2015-05-01

    This paper presents a systematic Structural Equation Modeling (SEM) based approach for Prospective Safety Performance Evaluation (PSPE) on construction sites, with causal relationships and interactions between enablers and the goals of PSPE taken into account. According to a sample of 450 valid questionnaire surveys from 30 Chinese construction enterprises, a SEM model with 26 items included for PSPE in the context of Chinese construction industry is established and then verified through the goodness-of-fit test. Three typical types of construction enterprises, namely the state-owned enterprise, private enterprise and Sino-foreign joint venture, are selected as samples to measure the level of safety performance given the enterprise scale, ownership and business strategy are different. Results provide a full understanding of safety performance practice in the construction industry, and indicate that the level of overall safety performance situation on working sites is rated at least a level of III (Fair) or above. This phenomenon can be explained that the construction industry has gradually matured with the norms, and construction enterprises should improve the level of safety performance as not to be eliminated from the government-led construction industry. The differences existing in the safety performance practice regarding different construction enterprise categories are compared and analyzed according to evaluation results. This research provides insights into cause-effect relationships among safety performance factors and goals, which, in turn, can facilitate the improvement of high safety performance in the construction industry. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Umeclidinium and Vilanterol Alone and in Combination: A Randomized Crossover Trial

    PubMed Central

    Kelleher, Dennis L.; Mehta, Rashmi S.; Jean-Francois, Bernadette M.; Preece, Andrew F.; Blowers, James; Crater, Glenn D.; Thomas, Paul

    2012-01-01

    Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β2 agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4–5 h for umeclidinium and median tlast of 1.5–2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone. Trial Registration Clinicaltrials.gov NCT00976144 PMID:23284643

  8. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

    PubMed

    Andrade, E L; Bento, A F; Cavalli, J; Oliveira, S K; Schwanke, R C; Siqueira, J M; Freitas, C S; Marcon, R; Calixto, J B

    2016-12-12

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

  9. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

    PubMed Central

    Andrade, E.L.; Bento, A.F.; Cavalli, J.; Oliveira, S.K.; Schwanke, R.C.; Siqueira, J.M.; Freitas, C.S.; Marcon, R.; Calixto, J.B.

    2016-01-01

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose. PMID:27982281

  10. First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288.

    PubMed

    Gee, Kelvin W; Olincy, Ann; Kanner, Richard; Johnson, Lynn; Hogenkamp, Derk; Harris, Josette; Tran, Minhtam; Edmonds, Stephen A; Sauer, William; Yoshimura, Ryan; Johnstone, Timothy; Freedman, Robert

    2017-04-01

    Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.

  11. Plutonium Finishing Plant safety evaluation report

    SciTech Connect

    Not Available

    1995-01-01

    The Plutonium Finishing Plant (PFP) previously known as the Plutonium Process and Storage Facility, or Z-Plant, was built and put into operation in 1949. Since 1949 PFP has been used for various processing missions, including plutonium purification, oxide production, metal production, parts fabrication, plutonium recovery, and the recovery of americium (Am-241). The PFP has also been used for receipt and large scale storage of plutonium scrap and product materials. The PFP Final Safety Analysis Report (FSAR) was prepared by WHC to document the hazards associated with the facility, present safety analyses of potential accident scenarios, and demonstrate the adequacy of safety class structures, systems, and components (SSCs) and operational safety requirements (OSRs) necessary to eliminate, control, or mitigate the identified hazards. Documented in this Safety Evaluation Report (SER) is DOE`s independent review and evaluation of the PFP FSAR and the basis for approval of the PFP FSAR. The evaluation is presented in a format that parallels the format of the PFP FSAR. As an aid to the reactor, a list of acronyms has been included at the beginning of this report. The DOE review concluded that the risks associated with conducting plutonium handling, processing, and storage operations within PFP facilities, as described in the PFP FSAR, are acceptable, since the accident safety analyses associated with these activities meet the WHC risk acceptance guidelines and DOE safety goals in SEN-35-91.

  12. Pharmacokinetic evaluation of formulated levodopa methyl ester nasal delivery systems.

    PubMed

    Lee, Yeon Hong; Kim, Kyung Hee; Yoon, In Kyung; Lee, Kyung Eun; Chun, In Koo; Rhie, Jeong Yeon; Gwak, Hye Sun

    2014-12-01

    The objective of this study was to investigate the pharmacokinetic characteristics of levodopa (L-dopa) from nasal powder formulations using highly water-soluble levodopa methyl ester hydrochloride (LDME). In vivo pharmacokinetic studies were carried out with formulated LDME nasal powders. After oral and intravenous administration of L-dopa and carbidopa and intranasal administration LDME to the rat, L-dopa concentrations were determined in plasma and the brain using high-performance liquid chromatography. The absolute bioavailabilities of nasal preparations with and without Carbopol were 82.4 and 66.7 %, respectively, which were much higher than that of oral delivery (16.2 %). The drug-targeting efficiencies [area under the curve (AUC) in brain/AUC in plasma] of L-dopa in the nasal formulations (0.98-1.08) were much higher than that of oral preparation (0.69). These results suggest that LDME nasal powder formulations would be useful delivery systems of L-dopa to the brain.

  13. Pharmacokinetic evaluation of almotriptan for the treatment of migraines.

    PubMed

    Negro, Andrea; Lionetto, Luana; D'Alonzo, Lidia; Casolla, Barbara; Marsibilio, Francesco; Vignaroli, Gabriele; Simmaco, Maurizio; Martelletti, Paolo

    2013-05-01

    Migraine is a multifactorial neurovascular disorder characterized by recurrent episodes of disabling pain attacks, accompanied with gastrointestinal, neurological systems dysfunction. The pharmacologic treatment of migraine is classically divided in the management of the acute attack and preventive strategies. Triptans represent a powerful pharmacological tool in acute migraine treatment. However, a significant portion of treated patients cannot have access to this class due to possible adverse affects. Today, a total of seven triptan molecules are available, representing a commonly prescribed migraine treatment. The authors take a systematic approach to discuss the pharmacodynamic and pharmacokinetic aspects of almotriptan . They consider the emerging data on the clinical efficacy in the treatment of migraine and menstrual-related migraine. The data were obtained by searching the following key words in MEDLINE: pharmacokinetic, pharmacodynamic, triptans, almotriptan, migraine, menstrual migraine, relatively to the period 1989 - 2012. The excellent efficacy and superior tolerability profile of almotriptan administered early offer a potential improvement over existing triptans for the symptomatic treatment of migraine attacks. Compared with other triptans, the different pathways involved in the metabolism of almotriptan ensure a limited variability of clinical response to the drug, making it less susceptible to the individual genomic background.

  14. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment.

    PubMed

    Panhuizen, I F; Gold, S J A; Buerkle, C; Snoeck, M M J; Harper, N J N; Kaspers, M J G H; van den Heuvel, M W; Hollmann, M W

    2015-05-01

    This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] <30 ml min(-1)) vs those with normal renal function (CLCR ≥80 ml min(-1)). Sugammadex 4 mg kg(-1) was administered at 1-2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T4/T1) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within -1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed. The intent-to-treat group comprised 67 patients (renal n=35; control n=32). Median (95% CI) time from sugammadex to recovery to T4/T1 ratio 0.9 was 3.1 (2.4-4.6) and 1.9 (1.6-2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6-2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg(-1)) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics. Sugammadex 4 mg kg(-1) provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex-rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population. NCT00702715. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. A new amoxicillin/clavulanate therapeutic system: preparation, in vitro and pharmacokinetic evaluation.

    PubMed

    Kerc, Janez; Opara, Jerneja

    2007-04-20

    A new peroral amoxicillin/clavulanate therapeutic system composed of immediate release tablet and controlled release floating capsule was developed and evaluated by in vivo bioavailability study. Pharmacokinetic (PK) parameters for amoxicillin and clavulanic acid of the new therapeutic systems: AUCt, AUCi, (AUCt/AUCi), Cmax, Tmax, kel, T(1/2) and additionally for amoxicillin T(4) and T(2) were calculated from the plasma levels. The study confirmed enhanced pharmacokinetic parameters of a newly developed therapeutic system containing 1500 mg of amoxicillin and 125 mg of clavulanic acid. Prolonged time over MIC of amoxicillin in relation to a regular immediate release amoxicillin/clavulanate formulation was confirmed.

  16. Pharmacokinetics, Safety and Cognitive Function Profile of Rupatadine 10, 20 and 40 mg in Healthy Japanese Subjects: A Randomised Placebo-Controlled Trial

    PubMed Central

    Täubel, Jörg; Ferber, Georg; Fernandes, Sara; Lorch, Ulrike; Santamaría, Eva; Izquierdo, Iñaki

    2016-01-01

    Introduction Rupatadine is a marketed second generation antihistamine, with anti-PAF activity, indicated for symptomatic treatment of allergic rhinitis and urticaria. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of rupatadine in healthy Japanese subjects after single and multiple oral doses. Methods In this randomised, double-blind, placebo-controlled study, 27 male and female healthy Japanese subjects were administered single and multiple escalating rupatadine dose of 10, 20 and 40 mg or placebo. Blood samples were collected at different time points for PK measurements and subjects were assessed for safety and tolerability. The effect of rupatadine on cognitive functioning was evaluated by means of computerized cognitive tests: rapid visual information processing (RVP), reaction time (RT), spatial working memory (SWM) and visual analogue scales (VAS). Results Exposure to rupatadine as measured by Cmax and AUC was found to increase in a dose dependent manner over the dose range of 10–40 mg for both single and multiple dose administration. The safety assessments showed that all treatment related side effects were of mild intensity and there were no serious adverse events (SAEs) or withdrawals due to treatment–emergent adverse events (TEAEs) in this study. The therapeutic dose of rupatadine did not show any CNS impairment in any of the cognitive tests. Conclusions This study demonstrated that rupatadine is safe and well tolerated by Japanese healthy subjects. The PK-PD profile confirmed previous experience with rupatadine. PMID:27632557

  17. Safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of a randomized, double-blind study.

    PubMed

    Quiros, J Antonio; Heyman, Melvin B; Pohl, John F; Attard, Thomas M; Pieniaszek, Henry J; Bortey, Enoch; Walker, Kelli; Forbes, William P

    2009-11-01

    : A multicenter, double-blind study was conducted to evaluate the safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate ulcerative colitis (UC). : Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI) were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by > or =3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. : Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large interpatient variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. : Balsalazide is well tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age.

  18. Safety, Efficacy, and Pharmacokinetics of Balsalazide in Pediatric Patients with Mild-to-Moderate Active Ulcerative Colitis: Results of a Randomized, Double-Blind Study

    PubMed Central

    Quiros, J. Antonio; Heyman, Melvin B.; Pohl, John F.; Attard, Thomas M.; Pieniaszek, Henry J.; Bortey, Enoch; Walker, Kelli; Forbes, William P.

    2012-01-01

    Objectives A multicenter, double-blind study was conducted to evaluate the safety, efficacy and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate UC. Methods Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI), were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by ≥3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. Results Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large inter-subject variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. Conclusions Balsalazide is well-tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age. PMID:19633577

  19. Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus.

    PubMed

    Scheen, André J

    2014-09-01

    Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

  20. Evaluation of the influence of sulfur fumigation on the pharmacokinetics of four active ingredients in Si Wu Tang.

    PubMed

    Pei, Ke; Cai, Hao; Liu, Xiao; Tu, Sicong; Cao, Gang; Li, Huan; Zhao, Yingying; Song, Xiaoqing; Lou, Yajing; Qiao, Fengxian; Cai, Baochang

    2015-01-01

    Sulfur fumigation may induce the decrease or the chemical transformation of some active ingredients of traditional Chinese medicines in vitro. Whether sulfur fumigation can cause the pharmacokinetic changes of the active ingredients in vivo is related to the efficacy and the safety of Chinese medicines' application clinically. A sensitive, specific, and accurate method for the simultaneous determination of paeoniflorin, ferulic acid, senkyunolide A, and senkyunolide I in rat plasma by ultra high performance liquid chromatography coupled with triple quadrupole mass spectrometry was developed to evaluate the influence of sulfur fumigation to Si Wu Tang for the first time. Each compound was extracted from plasma samples by liquid-liquid extraction with ethyl acetate, and the chromatographic separation was accomplished on an Agilent Extend C18 column with a linear gradient elution. The mass spectrometric detection and analysis were performed by using an AB Sciex triple quadrupole 5500 mass spectrometer in multiple reaction monitoring mode. The validated method was successfully applied to a pharmacokinetic study of four compounds in rats after oral administration of sun-dried and sulfur-fumigated Si Wu Tang. The results provided a meaningful basis for evaluating the affection of sulfur fumigation to the clinical application and the efficacy of Si Wu Tang. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate.

    PubMed

    Ruiz-Sáez, A; Hong, A; Arguello, A; Echenagucia, M; Boadas, A; Fabbrizzi, F; Minichilli, F; Bosch, N B

    2005-11-01

    Therapeutic options for developing countries have to assure an optimum safety and efficacy and low-cost antihaemophilic concentrates. A single blind randomized crossover study was carried out in 12 previously treated HB patients, comparing the pharmacokinetics (PK), thrombogenicity (TG) and safety of two plasma-derived double-inactivated (solvent/detergent heating at 100 degrees C, 30 min) factor IX (FIX) concentrates, UMAN COMPLEX DI (product A) [plasma-derived prothrombin concentrates (PCC)] and a high purity FIX concentrate AIMAFIX DI (product B, HPFIX). In a non-bleeding state, they received one single intravenous dose 50 IU FIX kg(-1) of PCC or HPFIX, and after a wash-out period of 14 days, the other product. We evaluated acute tolerance and determined PK parameters based on FIX levels measured over a 50 h postinfusion period. We studied fibrinogen, platelets, antithrombin, F1 + 2, TAT, D-dimer, over a 360 min postinfusion period. Ten cases remained in on-demand treatment for 6 months, five with PCC and five with HPFIX. PK and anti-FIX inhibitors were repeated at 3 and 6 months. No inhibitors were detected. PK values (PCC vs. HPFIX): clearence (CL; mL h(-1) kg(-1)) 5.2 +/- 1.4 vs. 6.5 +/- 1.4; the volume of distribution at steady state (mL kg(-1)) 154.9 +/- 54.9 vs. 197.5 +/- 72.5; mean residence time (h) 29.7 +/- 8.1 vs. 30.7 +/- 9.2; T(1/2) (h) 22.3 +/- 7 vs. 23.5 +/- 12.3; incremental recovery (IR; U dL(-1) U(-1) kg(-1)) 0.96 +/- 0.17 vs. 0.76 +/- 0.13. HPFIX showed significant lower IR and higher CL. There were no differences in PK at 3 and 6 months. In TG, significant increments in TAT and F1 + 2 at 30 min and 6 h were found with PCC. Product B PK results agrees with reported results for other HPFIX preparations. Use of PCC product A has to consider its thrombogenic activity.

  2. Safety evaluation of arch dam stability

    SciTech Connect

    Liu Defu

    1995-12-31

    The abutment sliding is the main form of failure in arch dams. Two approaches are used in defining and evaluating the stability safety factor which are the load safety factor Kp and strength safety factor Kf. So far, the Kp method is still the main method in stability model test of arch dams. This paper, to begin with the analysis of the stability formulas and the influence factors of stability in arch dams, will discuss in detail the merits and demerits of Kp and Kf methods and compare Kp with Kf for same structure. A new approach is proposed and the test steps existing problems and their solutions are all discussed.

  3. Pharmacokinetics and Safety of DW1029M, a Botanical Drug for the Treatment of Diabetic Nephropathy, Following Single Doses in Healthy Subjects.

    PubMed

    Kim, Yunjeong; Jeon, Ji-Young; Kim, Eun-Young; Lim, Cheol-Hee; Jang, Hwan Bong; Kim, Min-Gul

    2017-09-01

    DW1029M is a botanical extract of Morus albalinne root bark and Puerariae radix that is used for the treatment of diabetic nephropathy. This study evaluated the safety and pharmacokinetics of DW1029M following its administration in healthy Korean subjects. We conducted a randomized, open-label, single-dose, crossover phase 1 clinical study. During each period, subjects received 300, 600, or 1200 mg oral doses of DW1029M. Plasma concentrations of puerarin, daidzin, and daidzein were analyzed using a liquid chromatography-tandem mass spectrometry. Six healthy male subjects completed the study. The maximum concentration of the drug in the plasma (Cmax ) and area under the plasma drug concentration-time curve to the last measurable concentration (AUClast ) for puerarin, daidzin, and daidzein were assessed after oral administration of DW1029M. No serious adverse events or clinically or statistically significant adverse events associated with any of the drug levels were observed. The results of the measurement of vital signs, electrocardiogram, laboratory tests, and physical examinations indicated that no clinically significant changes occurred during this study. The DW1029M tablet was safe and well tolerated over a single dose range of 300-1200 mg. This pharmacokinetic study of a botanical drug may aid in the development of DW1029M. © 2017, The American College of Clinical Pharmacology.

  4. Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

    PubMed

    Akahori, Mizuki; Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Zhou, Wei; Sunkara, Gangadhar

    2017-06-01

    LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

  5. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis.

    PubMed

    Parasrampuria, Dolly A; Marbury, Thomas; Matsushima, Nobujo; Chen, Shuquan; Wickremasingha, Prachi K; He, Ling; Dishy, Victor; Brown, Karen S

    2015-04-01

    Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.

  6. Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

    PubMed Central

    Fordyce, Marshall; Garner, William; Vimal, Mona; Ling, Kah Hiing J.; Kearney, Brian P.; Ramanathan, Srinivasan

    2016-01-01

    Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIV-uninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, ≥90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (Cmax) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUCinf) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV Cmax and AUCinf were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens. PMID:27216057

  7. [Pharmacokinetics and safety of aripiprazole long-acting injection, following multiple deltoid administrations in schizophrenia patients in Japan].

    PubMed

    Ishigooka, Jun; Noda, Takamasa; Nishiyama, Kosuke; Tamaru, Noriko; Shima, Tomoko; Yamasaki, Yumiko; Tadori, Yoshihiro

    2016-06-01

    Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.

  8. Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study.

    PubMed

    Gupta, Neeraj; Goh, Yeow Tee; Min, Chang-Ki; Lee, Jae Hoon; Kim, Kihyun; Wong, Raymond S M; Chim, Chor Sang; Hanley, Michael J; Yang, Huyuan; Venkatakrishnan, Karthik; Hui, Ai-Min; Esseltine, Dixie-Lee; Chng, Wee Joo

    2015-09-04

    The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide-dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide-dexamethasone, in East Asian patients with relapsed/refractory MM. Adult patients with measurable disease who had received 1-3 prior lines of therapy received oral ixazomib on days 1, 8, and 15, lenalidomide (25 mg) on days 1-21, and dexamethasone (40 mg) on days 1, 8, 15, and 22, in 28-day cycles. Primary objectives were to characterize ixazomib plasma pharmacokinetics, determine the recommended phase 2/3 dose, and evaluate safety and tolerability. Forty-three patients were enrolled. No dose-limiting toxicities were reported for the first six patients receiving ixazomib (4.0 mg), confirming this as the recommended phase 2/3 dose. Ixazomib was rapidly absorbed with a median T max of 1.5 h on day 1 and 2.0 h on day 15 of cycle 1 and had a geometric mean terminal half-life of 6.1 days. Twenty-one (49%) patients had at least one drug-related grade ≥3 adverse event (AE); the most common were neutropenia (19%), diarrhea (14%), and thrombocytopenia (12%). Twenty-eight of 43 (65%) response-evaluable patients had at least a partial response. The recommended phase 2/3 dose for ixazomib was determined to be 4.0 mg. The all-oral combination of ixazomib plus lenalidomide-dexamethasone appeared active and well tolerated at 4.0 mg. Consequently, East Asian patients enrolled in phase 3 studies are receiving the same ixazomib dose as patients in other regions. This study is registered at NCT01645930.

  9. Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers

    PubMed Central

    Teng, Renli; Maya, Juan; Butler, Kathleen

    2013-01-01

    The results of two independent, randomized, two-period crossover, single-center studies, conducted to assess the pharmacokinetics of ticagrelor ± aspirin, inhibition of platelet aggregation (IPA) with ticagrelor/aspirin vs. clopidogrel/aspirin, and safety, tolerability, and bleeding times are reported here. In Study A (open-label), 16 volunteers received ticagrelor (50 mg bid Days 1–5; 200 mg bid Days 6–9; one 200 mg dose on Day 10) ± 300 mg qd aspirin (Days 1–10). In Study B (double-blind, double-dummy), 16 volunteers received aspirin (300 mg loading dose/75 mg qd Days 2–9) with either ticagrelor (200 mg bid Days 4–8, one 200 mg dose on Day 9) or clopidogrel (300 mg loading dose Day 4, 75 mg qd Days 5–9). At steady-state ticagrelor (50 mg bid, or 200 mg bid), concomitant aspirin (300 mg qd) had no effect on mean maximum plasma concentration (C max), median time to C max (t max), or mean area under the plasma concentration-time curve for the dosing interval (AUC0– τ) for ticagrelor and its primary metabolite, AR-C124910XX. Following 200 mg bid ticagrelor, mean C max and AUC0– τ for both parent and metabolite were comparable with co-administration of aspirin at 75 mg and 300 mg qd. Aspirin (300 mg qd) had no effect on IPA (ADP-induced) by ticagrelor. However, aspirin and ticagrelor had an additive effect on IPA (collagen-induced). Ticagrelor/aspirin increased bleeding times vs. baseline. Ticagrelor/aspirin co-administration was well tolerated at all dose combinations evaluated. In summary, the findings of this study demonstrate that co-administration of aspirin (300 mg qd) with ticagrelor (50 mg bid, or 200 mg bid) had no effect on ticagrelor pharmacokinetics or IPA (ADP-induced) by ticagrelor. PMID:23249161

  10. The Interagency Nuclear Safety Review Panel's Galileo safety evaluation report

    SciTech Connect

    Nelson, R.C.; Gray, L.B.; Huff, D.A.

    1989-01-01

    The safety evaluation report (SER) for Galileo was prepared by the Interagency Nuclear Safety Review Panel (INSRP) coordinators in accordance with Presidential directive/National Security Council memorandum 25. The INSRP consists of three coordinators appointed by their respective agencies, the Department of Defense, the Department of Energy (DOE), and the National Aeronautics and Space Administration (NASA). These individuals are independent of the program being evaluated and depend on independent experts drawn from the national technical community to serve on the five INSRP subpanels. The Galileo SER is based on input provided by the NASA Galileo Program Office, review and assessment of the final safety analysis report prepared by the Office of Special Applications of the DOE under a memorandum of understanding between NASA and the DOE, as well as other related data and analyses. The SER was prepared for use by the agencies and the Office of Science and Technology Policy, Executive Office of the Present for use in their launch decision-making process. Although more than 20 nuclear-powered space missions have been previously reviewed via the INSRP process, the Galileo review constituted the first review of a nuclear power source associated with launch aboard the Space Transportation System.

  11. Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects.

    PubMed

    Nomoto, Maiko; Pastino, Gina; Rege, Bhaskar; Aluri, Jagadeesh; Ferry, Jim; Han, David

    2017-03-24

    Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose-proportional manner over the dose range tested. After a single dose, platelet count increased in a dose-related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated. © 2017, The American College of Clinical Pharmacology.

  12. Effectiveness, Safety, and Pharmacokinetics of Quetiapine in Aggressive Children with Conduct Disorder

    ERIC Educational Resources Information Center

    Findling, Robert L.; Reed, Michael D.; O'Riordan, Mary Ann; Demeter, Christine A.; Stansbrey, Robert J.; McNamara, Nora K.

    2006-01-01

    Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale…

  13. Effectiveness, Safety, and Pharmacokinetics of Quetiapine in Aggressive Children with Conduct Disorder

    ERIC Educational Resources Information Center

    Findling, Robert L.; Reed, Michael D.; O'Riordan, Mary Ann; Demeter, Christine A.; Stansbrey, Robert J.; McNamara, Nora K.

    2006-01-01

    Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale…

  14. Pharmacokinetic and Toxicological Evaluation of a Zinc Gluconate-Based Chemical Sterilant Using In Vitro and In Silico Approaches.

    PubMed

    Araujo-Lima, Carlos F; Nunes, Rafael J M; Carpes, Raphael M; Aiub, Claudia A F; Felzenszwalb, Israel

    2017-01-01

    Sclerosing agents as zinc gluconate-based chemical sterilants (Infertile®) are used for chemical castration. This solution is injected into the animal testis, but there are not enough evidences of its safety profiles for the receivers. The present work aimed to establish the pharmacokinetics and toxicological activity of Infertile, using in vitro and in silico approaches. The evaluation at the endpoint showed effects in a dose-dependent manner. Since necrosis is potentially carcinogenic, the possible cell death mechanism could be apoptosis. Our data suggested that Infertile at 60 mM presented risk for animal health. Even though Infertile is a licensed product by the Brazilian Ministry of Agriculture, Livestock and Supply, it presented a high mutagenic potential. We suggest that the optimal dose must be less than 6 mM, once, at this concentration, no mutagenicity or genotoxicity was observed.

  15. Pharmacokinetic and Toxicological Evaluation of a Zinc Gluconate-Based Chemical Sterilant Using In Vitro and In Silico Approaches

    PubMed Central

    Araujo-Lima, Carlos F.; Nunes, Rafael J. M.; Carpes, Raphael M.

    2017-01-01

    Sclerosing agents as zinc gluconate-based chemical sterilants (Infertile®) are used for chemical castration. This solution is injected into the animal testis, but there are not enough evidences of its safety profiles for the receivers. The present work aimed to establish the pharmacokinetics and toxicological activity of Infertile, using in vitro and in silico approaches. The evaluation at the endpoint showed effects in a dose-dependent manner. Since necrosis is potentially carcinogenic, the possible cell death mechanism could be apoptosis. Our data suggested that Infertile at 60 mM presented risk for animal health. Even though Infertile is a licensed product by the Brazilian Ministry of Agriculture, Livestock and Supply, it presented a high mutagenic potential. We suggest that the optimal dose must be less than 6 mM, once, at this concentration, no mutagenicity or genotoxicity was observed. PMID:28197414

  16. Safety, Pharmacokinetics, Pharmacodynamics, and Activity of Navitoclax, a Targeted High Affinity Inhibitor of BCL-2, in Lymphoid Malignancies

    PubMed Central

    Wilson, Wyndham H.; O’Connor, Owen A.; Czuczman, Myron S.; LaCasce, Ann S.; Gerecitano, John F.; Leonard, John P.; Tulpule, Anil; Dunleavy, Kieron; Xiong, Hao; Chiu, Yi-Lin; Cui, Yue; Busman, Todd; Elmore, Steven W.; Rosenberg, Saul H.; Krivoshik, Andrew P.; Enschede, Sari H.; Humerickhouse, Rod A.

    2010-01-01

    SUMMARY Background BCL-2 family proteins play a central role in regulating clonal selection and survival of lymphocytes and are frequently over expressed in lymphomas. Navitoclax (ABT-263) is a targeted high-affinity small molecule that occupies the BH3 binding groove of BCL-2 and BCL-XL and inhibits their anti-apoptotic activity. Experimentally, navitoclax kills cells in a BAX/BAK-dependent manner and results in regression of lymphoid tumors in xenograft models. Methods This is a phase I dose-escalation study of navitoclax in patients with relapsed or refractory lymphoid malignancies. Study endpoints included safety, maximum tolerated dose (MTD), pharmacokinetic profile and clinical activity. In addition, mechanism-based pharmacodynamic effects on platelets and lymphocytes were assessed. Navitoclax was orally administered and assessed on an intermittent schedule of once daily for 14 days followed by 7 days off (14/21 days) or on a continuous once daily schedule (21/21 days). This trial is registered with ClinicalTrials.gov, number NCT00406809. Findings Fifty-five patients were enrolled, (median age 59 years, IQR 51–67), of whom two did not complete the first cycle and were not evaluable for assessment of dose-limiting toxicity (DLT). Common toxicities included grade 1/2 diarrhea and fatigue in 31 and 21 patients, respectively. Thrombocytopenia and neutropenia were the serious common toxicities with grade 3/4 observed in 29 and 17 patients, respectively. On the intermittent schedule (14/21), 5 DLT’s were observed; two due to hospitalizations for bronchitis and pleural effusion, and one each due to grade 3 transaminase elevation, grade 4 thrombocytopenia and grade 3 cardiac arrhythmia. Navitoclax caused a rapid and dose-dependent decline in peripheral platelets following initial drug exposure, followed by a rebound. To reduce the platelet nadir associated with intermittent dosing, a lead-in dose followed by continuous dosing (21/21 schedule) was examined. Three

  17. Safety evaluation of multilane arterials in Florida.

    PubMed

    Abdel-Aty, Mohamed; Devarasetty, Prem Chand; Pande, Anurag

    2009-07-01

    Resurfacing is one of the more common construction activities on highways. While its effect on riding quality on any type of roadway is obviously positive; its impact on safety as measured in terms of crashes is far from obvious. This study examines the safety effects of the resurfacing projects on multilane arterials with partially limited access. Empirical Bayes method, which is one of the most accepted approaches for conducting before-after evaluations, has been used to assess the safety effects of the resurfacing projects. Safety effects are estimated not only in terms of all crashes but also rear-end as well as severe crashes (crashes involving incapacitating and fatal injuries). The safety performance functions (SPFs) used in this study are negative binomial crash frequency estimation models that use the information on ADT, length of the segments, speed limit and number of lanes. These SPFs are segregated by crash groups (all, rear-end, and severe), length of the segments being evaluated, and land use (urban, suburban, and rural). The results of the analysis show that the resulting changes in safety following resurfacing projects vary widely. Evaluating additional improvements carried out with resurfacing activities showed that all (other than sidewalk improvements for total crashes) of them consistently led to improvements in safety of multilane arterial sections. It leads to the inference that it may be a good idea to take up additional improvements if it is cost effective to do them along with resurfacing. It was also found that the addition of turning lanes (left and/or right) and paving shoulders were two improvements associated with a project's relative performance in terms of reduction in rear-end crashes.

  18. Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation.

    PubMed

    Scheen, André J

    2013-03-01

    The first-choice drug therapy in the management of type 2 diabetes is metformin . However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly referred to as gliptins, offer new options for combined therapy with metformin. Linagliptin is the most recently launched gliptin, with a unique pharmacokinetic (PK) profile characterized by negligible renal excretion and is now also available as a fixed-dose combination (FDC) with metformin. An extensive literature search was performed to analyze the potential PK and pharmacodynamic interactions between linagliptin and metformin. Linagliptin and metformin may be administered together, either separately or as FDC supported by bioequivalence studies. Linagliptin and metformin are not prone to PK drug-drug interactions. Their coadministration improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metformin-related gastrointestinal side effects. The combination linaglitpin plus metformin, if not contraindicated (renal failure), may be used as first-line or second-line therapy in the management of type 2 diabetes. That being said, the durability of the glucose-lowering effect of this combination needs to be further explored in long-term controlled trials.

  19. Pharmacokinetic and pharmacodynamic evaluation of phencyclidine and its decadeutero variant

    SciTech Connect

    Cho, A.K.; Hiramatsu, M.; Pechnick, R.N.; Di Stefano, E.

    1989-07-01

    The role of metabolism in the in vivo actions of phencyclidine (PCP) was examined by comparing deuterium-substituted drug with drug of normal isotopic abundance. PCP elicits two responses that differ in their time course, ataxia, which is observable immediately after dosage, and hypothermia, which peaks approximately 90 to 120 min after drug administration. The role of metabolism in these responses was determined by comparing bioavailabilities of deuterium enriched (d10) and normal (d0) PCP with the two responses. Plasma concentration was determined after the i.v. and i.p. administration of d10 and d0 drug and the bioavailability of the d10 was found to be 1.3 to 1.5 times the d0. The clearance of the d10 was also smaller than the d0. The d10, which is pharmacologically equivalent in vitro, is metabolized more slowly than the d0 in vitro. The pharmacokinetic and pharmacodynamic bioavailabilities exhibited comparable isotope effects, indicating that both responses are due to the actions of the parent drug.

  20. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects.

    PubMed

    Sidharta, Patricia N; van Giersbergen, Paul L M; Dingemanse, Jasper

    2013-11-01

    This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies. © 2013, The American College of Clinical Pharmacology.

  1. Skin safety evaluation of laundry detergent products.

    PubMed

    Kwon, Seok; Holland, Daniela; Kern, Petra

    2009-01-01

    The conduct of a scientifically sound safety assessment of new ingredients and finished products is essential prior to their introduction into the marketplace. Such assessments are based on a risk assessment paradigm established by the National Academy of Science (NAS, 1983) that consists of a four-step process: hazard identification, dose-response assessment, exposure assessment, and risk characterization. This risk assessment paradigm has been (1) used as a framework for estimating an adverse health risk posed by environmental chemicals, and (2) applied to systemic toxicological endpoints. The general principles of risk assessment may be applied to skin safety evaluation of consumer products, considering that dermal toxicity is also a threshold phenomenon. This study describes a risk assessment-based approach for skin safety evaluation of laundry detergent products.

  2. Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults.

    PubMed

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2015-02-01

    Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction. This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study. Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events. Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the

  3. Insulin receptor antibody-iduronate 2-sulfatase fusion protein: pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys.

    PubMed

    Boado, Ruben J; Ka-Wai Hui, Eric; Zhiqiang Lu, Jeff; Pardridge, William M

    2014-11-01

    Mucopolysaccharidosis (MPS) Type II is caused by mutations in the gene encoding the lysosomal enzyme, iduronate 2-sulfatase (IDS). The majority of MPSII cases affect the brain. However, enzyme replacement therapy with recombinant IDS does not treat the brain, because IDS is a large molecule drug that does not cross the blood-brain barrier (BBB). To enable BBB penetration, IDS has been re-engineered as an IgG-IDS fusion protein, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, and the HIRMAb domain of the fusion protein acts as a molecular Trojan horse to ferry the fused IDS into brain from blood. The present study reports on the first safety pharmacology and pharmacokinetics study of the HIRMAb-IDS fusion protein. Juvenile male Rhesus monkeys were infused intravenously (IV) weekly for 26 weeks with 0, 3, 10, or 30 mg/kg of the HIRMAb-IDS fusion protein. The plasma clearance of the fusion protein followed a linear pharmacokinetics profile, which was equivalent either with measurements of the plasma concentration of immunoreactive HIRMAb-IDS fusion protein, or with assays of plasma IDS enzyme activity. Anti-drug antibody (ADA) titers were monitored monthly, and the ADA response was primarily directed against the variable region of the HIRMAb domain of the fusion protein. No infusion related reactions or clinical signs of immune response were observed during the course of the study. A battery of safety pharmacology, clinical chemistry, and tissue histopathology showed no signs of adverse events, and demonstrate the safety profile of chronic treatment of primates with 3-30 mg/kg weekly IV infusion doses of the HIRMAb-IDS fusion protein. © 2014 Wiley Periodicals, Inc.

  4. Liraglutide's safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

    PubMed

    Klein, David J; Battelino, Tadej; Chatterjee, D J; Jacobsen, Lisbeth V; Hale, Paula M; Arslanian, Silva

    2014-10-01

    The prevalence of type 2 diabetes (T2D) in youth is increasing. Treatment options beyond metformin and insulin are needed. The safety, tolerability, pharmacokinetics, and pharmacodynamics of liraglutide once daily in youth (10-17 years old) with T2D were investigated in a randomized, double-blind, placebo-controlled trial. Youth treated with diet/exercise alone or with metformin and having a hemoglobin A1c (HbA1c) level of 6.5-11% were randomized to liraglutide (n=14) or placebo (n=7). Starting at 0.3 mg/day, doses were escalated weekly to 0.6, 0.9, 1.2, and 1.8 mg/day (or placebo equivalent) for 5 weeks. Nineteen participants completed the trial. Baseline characteristics were similar between groups, with mean (SD) values for age of 14.8 (2.2) years, weight of 113.2 (35.6) kg (range, 57-214 kg), diabetes duration of 1.7 (1.4) years, and HbA1c level of 8.1% (1.2%). No serious adverse events (AEs), including severe hypoglycemia, occurred. Transient gastrointestinal AEs were most common at lower liraglutide doses during dose escalation. No significant changes in safety and tolerability parameters occurred. There was no evidence of pancreatitis or lipase elevations above three times the upper normal limit; calcitonin levels remained within the normal range. For liraglutide 1.8 mg, mean half-life was 12 h, and clearance was 1.7 L/h. After 5 weeks, the decline in HbA1c level was greater with liraglutide versus placebo (-0.86 vs. 0.04%, P=0.0007), whereas mean body weight remained stable (-0.50 vs. -0.54 kg, P=0.9703). Liraglutide was well tolerated in youth with T2D, with safety, tolerability, and pharmacokinetic profiles similar to profiles in adults.

  5. A randomized safety and pharmacokinetic trial of daily tenofovir 1% gel in term and near-term pregnancy

    PubMed Central

    Beigi, Richard H; Noguchi, Lisa M; Montgomery, Elizabeth; Biggio, Joseph; Hendrix, Craig W; Marzinke, Mark A; Dai, James Y; Pan, Jason; Na Ayudhya, Ratiya Kunjara; Schwartz, Jill L; Isaacs, Karen; Piper, Jeanna M; Watts, D Heather

    2016-01-01

    Introduction Vaginal tenofovir (TFV) 1% gel may reduce incident HIV-1 and herpes simplex virus 2 infection. Pregnancy may increase risk of HIV acquisition, and incident HIV in pregnancy potentiates perinatal HIV transmission. Our objective was to investigate the safety and pharmacokinetics of seven days of TFV 1% vaginal gel in term and near-term pregnancy. Methods Ninety-eight healthy pregnant women, stratified to a term cohort followed by a near-term cohort, were enrolled into a 2:1 randomized, double-blinded, placebo-controlled trial. Women received TFV or placebo gel for seven consecutive days with pharmacokinetic sampling on days 0 and 6. Maternal and cord blood were collected at delivery. Primary end points included laboratory and genital adverse events, adverse pregnancy and neonatal outcomes, and maternal TFV levels. Results Most adverse events were grade 1 and none of the grade 3 or 4 adverse events were related to study product. There was no significant difference in safety end points between the two pregnancy cohorts (p=0.18); therefore, their data were combined. Primary safety end point rates were similar for mothers randomized to the TFV gel vs placebo arm (72.7 and 68.8%, p=0.81). The same was true for newborns in the TFV gel vs placebo arms (4.5% vs 6.3%, p=0.66). All women randomized to TFV had quantifiable serum levels within eight hours of dosing, with low overall median (interquartile range) day 0 and day 6 peak values (3.8 (2.0 to 7.0) and 5.8 (2.6 to 9.4) ng/mL, respectively). Conclusions Daily TFV 1% vaginal gel use in term and near-term pregnancy appears to be safe and produces low serum drug levels. PMID:27658440

  6. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo).

    PubMed

    McEneny-King, Alanna; Foster, Gary; Iorio, Alfonso; Edginton, Andrea N

    2016-12-07

    Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remains to be determined. Rather, individualized prophylaxis has been suggested to improve both patient safety and resource utilization. However, uptake of this approach has been hampered by the demanding sampling schedules and complex calculations required to obtain individual estimates of pharmacokinetic (PK) parameters. The use of population pharmacokinetics (PopPK) can alleviate this burden by reducing the number of plasma samples required for accurate estimation, but few tools incorporating this approach are readily available to clinicians. The Web-accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) project aims to bridge this gap by providing a Web-accessible service for the reliable estimation of individual PK parameters from only a few patient samples. This service is predicated on the development of validated brand-specific PopPK models. We describe the data analysis plan for the development and evaluation of each PopPK model to be incorporated into the WAPPS-Hemo platform. The data sources and structure of the dataset are discussed first, followed by the procedures for handling both data below limit of quantification (BLQ) and absence of such BLQ data. Next, we outline the strategies for building the appropriate structural and covariate models, including the possible need for a process algorithm when PK behavior varies between subjects or significant covariates are not provided. Prior to use in a prospective manner, the models will undergo extensive evaluation using a variety of techniques such as diagnostic plots, bootstrap analysis and cross-validation. Finally, we describe the incorporation of a validated PopPK model into the Bayesian post hoc model to

  7. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)

    PubMed Central

    McEneny-King, Alanna; Foster, Gary; Edginton, Andrea N

    2016-01-01

    Background Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remains to be determined. Rather, individualized prophylaxis has been suggested to improve both patient safety and resource utilization. However, uptake of this approach has been hampered by the demanding sampling schedules and complex calculations required to obtain individual estimates of pharmacokinetic (PK) parameters. The use of population pharmacokinetics (PopPK) can alleviate this burden by reducing the number of plasma samples required for accurate estimation, but few tools incorporating this approach are readily available to clinicians. Objective The Web-accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) project aims to bridge this gap by providing a Web-accessible service for the reliable estimation of individual PK parameters from only a few patient samples. This service is predicated on the development of validated brand-specific PopPK models. Methods We describe the data analysis plan for the development and evaluation of each PopPK model to be incorporated into the WAPPS-Hemo platform. The data sources and structure of the dataset are discussed first, followed by the procedures for handling both data below limit of quantification (BLQ) and absence of such BLQ data. Next, we outline the strategies for building the appropriate structural and covariate models, including the possible need for a process algorithm when PK behavior varies between subjects or significant covariates are not provided. Prior to use in a prospective manner, the models will undergo extensive evaluation using a variety of techniques such as diagnostic plots, bootstrap analysis and cross-validation. Finally, we describe the incorporation of a validated PopPK model into the

  8. Safety evaluation of yeast glutaminase.

    PubMed

    Ohshita, K; Nakajima, Y; Yamakoshi, J; Kataoka, S; Kikuchi, M; Pariza, M W

    2000-08-01

    The consumption of soy and soy products (including soy sauce) has been increasing in Western countries due to purported health benefits of soy (cancer protective, estrogenic effects). In addition to providing soy proteins and isoflavones, soy sauce also functions as a flavor enhancer and is able to impart a "umami" taste. Glutaminases are used in the production of soy sauce and enzymatically hydrolyzed protein. The glutaminases described herein were produced from the cultured broth of Cryptococcus albidus (ATCC-20293) which is designated as CK, a mutant of C. albidus (ATCC-20293) which is designated as CK-D10 and the newly isolated Cryptococcus sp. NISL-3771 which is designated as TK. All three preparations (CK, CK-D10 and TK) were evaluated for pathogenicity and virulence in mice and were found to be non-pathogenic. The acute LD(50)s for CK in male mice was greater than 4.8 g/kg body weight and for female mice was greater than 6.5 g/kg body weight. Acute LD(50)s for CK and CK-D10 in male and female rats was greater than 7.5 g/kg body weight, and that for TK was greater than 10 g/kg body weight. Subchronic (90-day) feeding studies (wherein the glutaminases were presented as dietary admixtures) were conducted in mice and rats. The NOAEL for CK in mice was 7.5 g/kg body weight/day. The NOAELs in rats were as follows: for CK, 9 g/kg body weight/day; for CK-D10, 1.2 g/kg body weight/day, and for TK, 8 g/kg body weight/day. Mice received CK as a dietary admixture at levels of 0, 1.0 and 10.0% for 1 year. The NOAEL was 13 g/kg body weight/day. The glutaminases from C. albidus described herein demonstrate very low toxicity.

  9. Safety evaluation of superabsorbent baby diapers.

    PubMed

    Kosemund, Kirstin; Schlatter, Harald; Ochsenhirt, Jennifer L; Krause, Edburga L; Marsman, Daniel S; Erasala, Geetha N

    2009-03-01

    Superabsorbent disposable baby diapers are sophisticated, well-engineered products that provide many benefits including convenience, comfort, exceptional leakage protection, improved hygiene and skin care benefits compared with cloth diapers. Safety assurance is an integral part of the diaper development process at Procter & Gamble, with the goal of ensuring safety for both caregivers and babies. A systematic, stepwise approach to safety assessment starts with a thorough evaluation of new design features and materials, using the principles of general risk assessment including, as appropriate, controlled trials to assess clinical endpoints or independent scientific review of safety data. The majority of the diaper materials are polymers that are safe and do not have inherent toxicity issues. Trace amounts of non-polymeric materials, such as colorants, are assessed based on their skin contact potential. New materials or design features are introduced in marketed products only if they have been shown to be safe under the conditions of recommended or foreseeable use. The product safety continues to be confirmed after launch by means of in-market monitoring. This article provides a broad overview of human safety exposure-based risk assessment used at Procter & Gamble for absorbent hygiene products.

  10. Pharmacokinetic evaluation of pregabalin for the treatment of generalized anxiety disorder.

    PubMed

    Buoli, Massimiliano; Caldiroli, Alice; Serati, Marta

    2017-03-01

    Pregabalin is an alternative compound to SSRIs and SNRIs for the first-line treatment of generalized anxiety disorder (GAD). Areas covered: We describe the pharmacokinetic properties of pregabalin and their implications for the treatment of GAD. A search in the main database sources (Medline, ISI, Web of Knowledge and Medscape) was performed in order to obtain a comprehensive and balanced evaluation about the clinical implications of the pharmacokinetic properties of pregabalin in the treatment of GAD. The word "pregabalin" was associated with "pharmacokinetics", "interactions"', "GAD", "anxiety" and "tolerability". No restriction criteria were established in relation to methodology or publication year. Only English-language articles were selected. Expert opinion: Pregabalin is a safe and efficacious compound for GAD treatment. Short half-life (preventing persistence of side effects), absence of active metabolites and no interactions with CYP450 enzymatic system are all favorable pharmacokinetic properties for the treatment of GAD patients, including those with comorbid depressive symptoms or medical conditions. On the other hand, prescription of pregabalin should be handled with caution to minimize the incidence of renal impairment (especially in elderly patients), where a history of substance misuse or concomitant medications (e.g. anti-hypertensives or some antibiotics) are risk factors that can affect renal function.

  11. When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

    PubMed

    Stern, Stephan T; Martinez, Marilyn N; Stevens, David M

    2016-12-01

    Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation.

  12. 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.

  13. Evaluation of Pharmacokinetic Interaction between PA-824 and Midazolam in Healthy Adult Subjects

    PubMed Central

    Winter, Helen; Egizi, Erica; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J.; Severynse-Stevens, Diana; Pauli, Elliott

    2013-01-01

    This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC0–t, AUC0–∞, and Cmax for midazolam and 1-hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of Cmax, AUC0–t, and AUC0–∞ parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The Cmax of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs. PMID:23689718

  14. Pharmacokinetic Evaluation of Oral Dantrolene in the Dog

    PubMed Central

    Haraschak, Jenica L.; Langston, Vernon C.; Wang, Ran; Riggs, Caitlin; Fellman, Claire; Ross, Matthew K.; Bulla, Camilo; Lunsford, Kari; Mackin, Andrew; Archer, Todd

    2014-01-01

    The pharmacokinetics of dantrolene and its active metabolite, 5-hydroxydantrolene, after a single oral dose of either 5 mg/kg or 10 mg/kg of dantrolene were determined. The effects of exposure to dantrolene and 5-hydroxydantrolene on activated whole blood gene expression of the cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (Cmax) was 0.43 µg/ml, terminal half-life (t1/2) was 1.26 hrs, and area under the time-concentration curve (AUC) was 3.87 µg hr/mL. For the 10 mg/kg dose, Cmax was 0.65 µg/ml, t1/2 was 1.21 hrs, and AUC was 5.94 µg hr/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t1/2, for example, ranged from 0.43 to 6.93 hrs, Cmax ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole blood expression of IL-2 and IFN-γ as measured by qRT-PCR was markedly suppressed following exposure to very high concentrations (30 µg/mL and 50 µg/mL, respectively) of both dantrolene and 5-hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing. PMID:24219828

  15. Pharmacokinetic evaluation of oral dantrolene in the dog.

    PubMed

    Haraschak, J L; Langston, V C; Wang, R; Riggs, C; Fellman, C; Ross, M K; Bulla, C; Lunsford, K; Mackin, A; Archer, T

    2014-06-01

    The pharmacokinetics of dantrolene and its active metabolite, 5-hydroxydantrolene, after a single oral dose of either 5 or 10 mg/kg of dantrolene was determined. The effects of exposure to dantrolene and 5-hydroxydantrolene on activated whole-blood gene expression of the cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (Cmax ) was 0.43 μg/mL, terminal half-life (t1/2 ) was 1.26 h, and area under the time-concentration curve (AUC) was 3.87 μg·h/mL. For the 10 mg/kg dose, Cmax was 0.65 μg/mL, t1/2 was 1.21 h, and AUC was 5.94 μg·h/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t1/2 , for example, ranged from 0.43 to 6.93 h, Cmax ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole-blood expression of IL-2 and IFN-γ as measured by qRT-PCR was markedly suppressed following exposure to very high concentrations (30 and 50 μg/mL, respectively) of both dantrolene and 5-hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing. © 2013 John Wiley & Sons Ltd.

  16. Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers.

    PubMed

    Ishida, Natsuko; Kobayashi, Erina; Kondo, Yuya; Matsushita, Ryo; Komai, Kiyonobu

    2015-08-01

    3,4-diaminopyridine (3,4-DAP) is commonly used for treating neuromuscular diseases, such as the Lambert-Eaton myasthenic syndrome, but the pharmacokinetics of 3,4-DAP base have not been investigated. We therefore studied 3,4-DAP base pharmacokinetics in healthy Japanese volunteers. In this crossover study, we administered a single oral dose of 10 or 20 mg 3,4-DAP base to healthy Japanese volunteers (n = 5) after food intake, or 10 mg 3,4-DAP to fasting individuals. We measured serum 3,4-DAP concentrations, performed electrocardiography (ECG), and administered questionnaires. After administration of 10 or 20 mg 3,4-DAP following food intake, the maximum serum concentrations (Cmax) were 8.09 ± 4.47 ng/mL and 35.8 ± 15.7 ng/mL, respectively (mean ± standard deviation; SD), and the areas under the serum concentration-time curve (extrapolated to infinity) were 639 ± 213 ng x min/mL and 2,097 ± 936 ng x min/mL (mean ± SD), respectively. Administration to fasted individuals indicated that food intake did not significantly alter 3,4-DAP pharmacokinetics. ECG showed no clinically significant changes, but PR intervals were prolonged in all cases. Two out of 5 subjects showed perioral paresthesia symptoms after administration of 20 mg 3,4-DAP. This study indicated that 3,4-DAP base pharmacokinetics were non-linear. Although no clinically significant changes in ECG were observed, it is advisable to perform ECG periodically during 3,4-DAP administration in order to monitor cardiac function. Moreover, the development of perioral paresthesia may be dependent on the dose of 3,4-DAP used.

  17. Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study.

    PubMed

    Massard, Christophe; Penttinen, Heidi M; Vjaters, Egils; Bono, Petri; Lietuvietis, Vilnis; Tammela, Teuvo L; Vuorela, Annamari; Nykänen, Pirjo; Pohjanjousi, Pasi; Snapir, Amir; Fizazi, Karim

    2016-05-01

    ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600mg twice daily ODM-201 taken with food in capsules. We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. The capsule:TabA ratio of area under the concentration-time curve from time zero to the last sample at 48h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule:TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (≥50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n=4 [13%]) and nausea (n=4 [13%]). The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600mg twice daily in patients with non-mCRPC is ongoing. Copyright © 2015 European Association

  18. Safety, pharmacokinetics and pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and postmenopausal women.

    PubMed

    Clark, Richard V; Walker, Ann C; Andrews, Susan; Turnbull, Philip; Wald, Jeffrey A; Magee, Mindy H

    2017-10-01

    Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of the SARM GSK2881078. In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0.05 mg, 0.2 mg then 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg, or placebo; in women (n = 24) they were 0.24 mg, 0.35 mg, or placebo (7 days for 0.5 mg, 14 days for other doses). PK analysis showed dose-proportional increases in exposure and a long >100-h half-life. No significant effects on vital signs, electrocardiograms, cardiac telemetry or standard clinical laboratory studies were observed. A dose-response effect was observed on lowering both high-density lipoprotein and sex hormone-binding globulin. In females at 0.35 mg, differences from placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l(-1) and -39.1 (-48.5, -29.7) nmol l(-1) , respectively. Women showed greater sensitivity to these parameters at lower doses than men. Drug-related adverse events (AEs) were mild. One woman developed a drug rash and was withdrawn. Two men had elevated creatine phosphokinase after physical exertion during follow-up. A serious AE occurred in a subject on placebo. These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM. © 2017 The British Pharmacological Society.

  19. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers.

    PubMed

    Frey, Reiner; Mück, Wolfgang; Unger, Sigrun; Artmeier-Brandt, Ulrike; Weimann, Gerrit; Wensing, Georg

    2008-12-01

    Preclinical data indicate that the nitric oxide-independent soluble guanylate cyclase activator cinaciguat (BAY 58-2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy-six healthy volunteers were included in this randomized, placebo-controlled study. Cinaciguat (50-250 microg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four-hour infusions (50-250 microg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150-250 microg/h), 4-hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose-proportionality with low interindividual variability. Plasma concentrations declined below 1.0 microg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.

  20. Psychomotor effects, pharmacokinetics and safety of the orexin receptor antagonist suvorexant administered in combination with alcohol in healthy subjects.

    PubMed

    Sun, Hong; Yee, Ka Lai; Gill, Sean; Liu, Wen; Li, Xiaodong; Panebianco, Deborah; Mangin, Eric; Morrison, Dennis; McCrea, Jacqueline; Wagner, John A; Troyer, Matthew D

    2015-11-01

    A double-blind crossover study investigated psychomotor effects, pharmacokinetics, and safety of the orexin receptor antagonist suvorexant with and without alcohol. Healthy adults (n=31) were randomized to receive placebo or suvorexant (40 mg) plus placebo solution or alcohol (0.7 g/kg) in each of four treatments (single doses; morning administration). The US Food and Drug Administration approved suvorexant dose is 10 mg (up to 20 mg) daily. Pharmacodynamic effects were assessed using tests of digit vigilance (DVT; primary endpoint), choice reaction time, digit symbol substitution, numeric working memory, immediate/delayed word recall, body sway and subjective alertness. Suvorexant alone did not significantly affect DVT reaction time, but did impact some pharmacodynamic tests. Suvorexant with alcohol increased reaction time versus either alone (mean difference at 2 h: 44 ms versus suvorexant, p<0.001; 24 ms, versus alcohol, p<0.05) and had additive negative effects on tests of vigilance, working/episodic memory, postural stability and alertness. No effects of suvorexant alone or with alcohol were observed by 9 h. No important changes in pharmacokinetic parameters were observed upon co-administration. All treatments were generally well tolerated without serious adverse events. In conclusion, co-administration of 40 mg suvorexant and 0.7 g/kg alcohol had additive negative psychomotor effects. Patients are advised not to consume alcohol with suvorexant.

  1. Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial.

    PubMed

    Awada, Ahmad; Gil, Thierry; Whenham, Nicolas; Van Hamme, Julie; Besse-Hammer, Tatiana; Brendel, Erich; Delesen, Heinz; Joosten, Miranda C; Lathia, Chetan D; Loembé, Bienvenu A; Piccart-Ghebart, Martine; Hendlisz, Alain

    2011-12-01

    Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.

  2. Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
.

    PubMed

    Kulmatycki, Kenneth M; Langenickel, Thomas; Ng, Wai Hong; Pal, Parasar; Zhou, Wei; Lin, Tsu-Han; Rajman, Iris; Chandra, Priyamvada; Sunkara, Gangadhar

    2017-09-01

    To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
.

  3. Safety, Pharmacokinetics, and Pharmacodynamic Effects of a Selective TGR5 Agonist, SB-756050, in Type 2 Diabetes.

    PubMed

    Hodge, Rebecca J; Lin, Jiang; Vasist Johnson, Lakshmi S; Gould, Elizabeth P; Bowers, Gary D; Nunez, Derek J

    2013-07-01

    TGR5 is a bile acid receptor and a potential target for the treatment of type 2 diabetes (T2D). We report here the safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in patients with T2D. Fifty-one subjects were randomized to receive either placebo or one of four doses of SB-756050 for 6 days. A single 100 mg dose of sitagliptin was co-administered on Day 6 to all subjects. SB-756050 was well-tolerated; it was readily absorbed, exhibited nonlinear pharmacokinetics with a less than dose-proportional increase in plasma exposure above 100 mg, and demonstrated no significant changes in exposure when co-administered with sitagliptin. SB-756050 demonstrated highly variable pharmacodynamic effects both within dose groups and between doses, with increases in glucose seen at the two lowest doses and no reduction in glucose seen at the two highest doses. The glucose effects of SB-756050 + sitagliptin were comparable to those of sitagliptin alone, even though gut hormone plasma profiles were different. This study was registered at ClinicalTrials.gov (NCT00733577).

  4. Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials

    PubMed Central

    Miyasaka, Nobuyuki; Kawai, Shinichi; Yuasa, Hirotoshi; Yamashita, Noriaki; Sugiyama, Noriko; Wagerle, Lorin Craig; Vlahos, Bonnie; Wajdula, Joseph

    2015-01-01

    Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA. PMID:24842477

  5. Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.

    PubMed Central

    Murdoch, D L; Thomson, G D; Thompson, G G; Murray, G D; Brodie, M J; McInnes, G T

    1991-01-01

    1. Potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol were evaluated in two double-blind, randomised, balanced, crossover studies employing the same six healthy males. 2. The first study examined the effect of repeated propranolol administration on the pharmacodynamics and pharmacokinetics of verapamil after single oral and intravenous doses. The second explored the pharmacodynamics and pharmacokinetics of verapamil and propranolol alone and in combination after single and repeated oral doses. 3. The magnitude of the prolongation of PR interval induced by oral and intravenous verapamil was not affected by pre-treatment with propranolol. When verapamil and propranolol were co-administered as single doses, effects on PR interval were additive but, following repeated doses, a trend towards greater than additive prolongation was seen. The arithmetic sum of the effects of the two drugs was 23% (95% C.I. 8-38%) but the measured increase after the combination was 40% (95% C.I. 26-54%). 4. The extent of reduction in heart rate and blood pressure at rest and after exercise following repeated doses of propranolol was not influenced by single oral or intravenous doses of verapamil. The heart rate and blood pressure responses to single and repeated oral doses of verapamil and propranolol in combination were significantly greater than those after either drug alone and approximated to the arithmetic sum of the individual responses. 5. Although repeated administration of propranolol reduced hepatic blood flow as assessed by indocyanine green clearance, there was no evidence of an interaction between the drugs at this level. 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol. After single doses of verapamil and propranolol in combination, the maximum plasma concentration of propranolol was increased and the oral clearance of verapamil reduced. No pharmacokinetic interaction was

  6. Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors.

    PubMed

    Juric, Dejan; Dienstmann, Rodrigo; Cervantes, Andres; Hidalgo, Manuel; Messersmith, Wells; Blumenschein, George R; Tabernero, Josep; Roda, Desamparados; Calles, Antonio; Jimeno, Antonio; Wang, Xiaodong; Bohórquez, Sandra Sanabria; Leddy, Cecilia; Littman, Catherine; Kapp, Amy V; Shames, David S; Penuel, Elicia; Amler, Lukas C; Pirzkall, Andrea; Baselga, José

    2015-06-01

    The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non-small cell lung cancer (n = 3). MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer. ©2015 American Association for Cancer Research.

  7. Safety, tolerability, and pharmacokinetics of SMT C1100, a 2‐arylbenzoxazole utrophin modulator, following single‐ and multiple‐dose administration to healthy male adult volunteers

    PubMed Central

    Tinsley, Jon; Robinson, Neil; Davies, Kay E.

    2015-01-01

    Abstract SMT C1100 is a small molecule utrophin modulator in development to treat Duchenne muscular dystrophy. This study evaluated the safety, tolerability, and pharmacokinetics of SMT C1100 in healthy volunteers. This double‐blind, placebo‐controlled Phase 1 study comprised: Part 1, an escalating, single‐dose with/without fasting involving 50 mg/kg, 100 mg/kg, 200 mg/kg, and 400 mg/kg doses; and Part 2, a multiple 10 day dose evaluation involving 100 mg/kg bid and 200 mg/kg bid doses. Adverse events were recorded. SMT C1100 was absorbed rapidly following single and multiple oral doses, with median tmax attained within 2–3.5 hour across all doses. Considerable variability of pharmacokinetic parameters was noted among subjects. Following single doses, systemic exposure increased in a sub‐proportional manner, with the 8.0‐fold dose increment resulting in 2.7‐ and 2.4‐fold increases in AUC0‐∞ and Cmax, respectively. AUC0‐∞ and Cmax were estimated as 4.2‐ and 4.8‐fold greater, respectively, following food. Systemic exposure reduced upon repeat dosing with steady‐state concentrations achieved within 3–5 days of multiple bid dosing. No serious or severe adverse events were reported. SMT C1100 was safe and well tolerated with plasma concentrations achieved sufficient to cause a 50% increase in concentrations of utrophin in cells in vitro. PMID:25651188

  8. Safety, tolerability, and pharmacokinetics of SMT C1100, a 2-arylbenzoxazole utrophin modulator, following single- and multiple-dose administration to healthy male adult volunteers.

    PubMed

    Tinsley, Jon; Robinson, Neil; Davies, Kay E

    2015-06-01

    SMT C1100 is a small molecule utrophin modulator in development to treat Duchenne muscular dystrophy. This study evaluated the safety, tolerability, and pharmacokinetics of SMT C1100 in healthy volunteers. This double-blind, placebo-controlled Phase 1 study comprised: Part 1, an escalating, single-dose with/without fasting involving 50 mg/kg, 100 mg/kg, 200 mg/kg, and 400 mg/kg doses; and Part 2, a multiple 10 day dose evaluation involving 100 mg/kg bid and 200 mg/kg bid doses. Adverse events were recorded. SMT C1100 was absorbed rapidly following single and multiple oral doses, with median tmax attained within 2-3.5 hour across all doses. Considerable variability of pharmacokinetic parameters was noted among subjects. Following single doses, systemic exposure increased in a sub-proportional manner, with the 8.0-fold dose increment resulting in 2.7- and 2.4-fold increases in AUC0-∞ and Cmax , respectively. AUC0-∞ and Cmax were estimated as 4.2- and 4.8-fold greater, respectively, following food. Systemic exposure reduced upon repeat dosing with steady-state concentrations achieved within 3-5 days of multiple bid dosing. No serious or severe adverse events were reported. SMT C1100 was safe and well tolerated with plasma concentrations achieved sufficient to cause a 50% increase in concentrations of utrophin in cells in vitro. © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  9. 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.

  10. Safety and Population Pharmacokinetic Analysis of Intravenous Acetaminophen in Neonates, Infants, Children, and Adolescents With Pain or Fever

    PubMed Central

    Zuppa, Athena F.; Hammer, Gregory B.; Barrett, Jeffrey S.; Kenney, Brian F.; Kassir, Nastya; Mouksassi, Samer; Royal, Mike A.

    2011-01-01

    OBJECTIVES The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration. PMID:22768009

  11. Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or Fever.

    PubMed

    Zuppa, Athena F; Hammer, Gregory B; Barrett, Jeffrey S; Kenney, Brian F; Kassir, Nastya; Mouksassi, Samer; Royal, Mike A

    2011-10-01

    The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

  12. Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration

    PubMed Central

    Peters-Strickland, Timothy; Nylander, Anna-Greta; Baker, Ross A.; Eramo, Anna; Jin, Na; Bricmont, Patricia; Repella, Jennifer; McQuade, Robert D.; Hertel, Peter; Larsen, Frank

    2017-01-01

    Abstract Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia. Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466). Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d. Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia. PMID:28204607

  13. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults.

    PubMed

    Ledgerwood, J E; Coates, E E; Yamshchikov, G; Saunders, J G; Holman, L; Enama, M E; DeZure, A; Lynch, R M; Gordon, I; Plummer, S; Hendel, C S; Pegu, A; Conan-Cibotti, M; Sitar, S; Bailer, R T; Narpala, S; McDermott, A; Louder, M; O'Dell, S; Mohan, S; Pandey, J P; Schwartz, R M; Hu, Z; Koup, R A; Capparelli, E; Mascola, J R; Graham, B S

    2015-12-01

    VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n = 18), the clearance was 0.016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies.

  14. Comparison of Pharmacokinetics and Safety of Voriconazole Intravenous-to-Oral Switch in Immunocompromised Adolescents and Healthy Adults ▿

    PubMed Central

    Driscoll, Timothy A.; Frangoul, Haydar; Nemecek, Eneida R.; Murphey, Donald K.; Yu, Lolie C.; Blumer, Jeffrey; Krance, Robert A.; Baruch, Alice; Liu, Ping

    2011-01-01

    The current voriconazole dosing recommendation in adolescents is based on limited efficacy and pharmacokinetic data. To confirm the appropriateness of dosing adolescents like adults, a pharmacokinetic study was conducted in 26 immunocompromised adolescents aged 12 to <17 years following intravenous (IV) voriconazole to oral switch regimens: 6 mg/kg IV every 12 h (q12h) on day 1 followed by 4 mg/kg IV q12h, then switched to 300 mg orally q12h. Area under the curve over a 12-hour dosing interval (AUC0–12) was calculated using a noncompartmental method and compared to the value for adults receiving the same dosing regimens. On average, the AUC0–12 in adolescents after the first loading dose on day 1 and at steady state during IV treatment were 9.14 and 22.4 μg·h/ml, respectively (approximately 34% and 36% lower, respectively, than values for adults). At steady state during oral treatment, adolescents also had lower average exposure than adults (16.7 versus 34.0 μg·h/ml). Larger intersubject variability was observed in adolescents than in adults. There was a slight trend for some young adolescents with low body weight to have lower voriconazole exposure. It is likely that these young adolescents may metabolize voriconazole more similarly to children than to adults. Overall, with the same dosing regimens, voriconazole exposures in the majority of adolescents were comparable to those in adults. The young adolescents with low body weight during the transitioning period from childhood to adolescence (e.g., 12 to 14 years old) may need to receive higher doses to match the adult exposures. Safety of voriconazole in adolescents was consistent with the known safety profile of voriconazole. PMID:21911570

  15. Safety evaluation of natural flavour complexes.

    PubMed

    Smith, R L; Adams, T B; Cohen, S M; Doull, J; Feron, V J; Goodman, J I; Hall, R L; Marnett, L J; Portoghese, P S; Waddell, W J; Wagner, B M

    2004-04-01

    Natural flavour complexes (NFCs) are chemical mixtures obtained by applying physical separation methods to botanical sources. Many NFCs are derived from foods. In the present paper, a 12-step procedure for the safety evaluation of NFCs, 'the naturals paradigm', is discussed. This procedure, which is not intended to be viewed as a rigid check list, begins with a description of the chemical composition of the commercial product, followed by a review of the data on the history of dietary use. Next, each constituent of an NFC is assigned to one of 33 congeneric groups of structurally related substances and to one of three classes of toxic potential, each with its own exposure threshold of toxicological concern. The group of substances of unknown structure is placed in the class of greatest toxic potential. In subsequent steps, for each congeneric group the procedure determines the per capita intake, considers metabolic pathways and explores the need and availability of toxicological data. Additional toxicological and analytical data may be required for a comprehensive safety evaluation. The procedure concludes with an evaluation of the NFC in its entirety, also considering combined exposure to congeneric groups. The first experiences with the use of this procedure are very promising. Future safety evaluations of larger numbers of NFCs will indicate the usefulness of the system, either in its present form or in a form modified on the basis of experience.

  16. A Cell-Based Pharmacokinetics Assay for Evaluating Tubulin-Binding Drugs

    PubMed Central

    Wang, Yuwei; Liu, Jihua; Zhang, Jun; Wang, Liping; Chan, Jonathon; Wang, Hai; Jin, Yi; Yu, Lei; Grainger, David W.; Ying, Wenbin

    2014-01-01

    Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug preclinical screening and clinical efficacy assessments. Here we report a whole cell-based method to assess drugs that disturb microtubule dynamics to better understand different formulation-mediated intracellular drug release profiles. As proof of concept for this approach, we compared the well-known taxane class of anti-microtubule drugs based on paclitaxel (PTX), including clinically familiar albumin nanoparticle-based Abraxane™, and a polymer nanoparticle-based degradable paclitaxel carrier, poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX, also known as CT-2103) versus control PTX. This in vitro cell-based evaluation of PTX efficacy includes determining the cellular kinetics of tubulin polymerization, relative populations of cells under G2 mitotic arrest, cell proliferation and total cell viability. For these taxane tubulin-binding compounds, the kinetics of cell microtubule stabilization directly correlate with G2 arrest and cell proliferation, reflecting the kinetics and amounts of intracellular PTX release. Each individual cell-based dose-response experiment correlates with published, key therapeutic parameters and taken together, provide a comprehensive understanding of drug intracellular pharmacokinetics at both cellular and molecular levels. This whole cell-based evaluating method is convenient, quantitative and cost-effective for evaluating new formulations designed to optimize cellular pharmacokinetics for drugs perturbing tubulin polymerization as well as assisting in explaining drug mechanisms of action at cellular levels. PMID:24688312

  17. Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers

    PubMed Central

    Chinsangaram, Jarasvech; Honeychurch, Kady M.; Tyavanagimatt, Shanthakumar R.; Leeds, Janet M.; Bolken, Tove' C.; Jones, Kevin F.; Jordan, Robert; Marbury, Thomas; Ruckle, Jon; Mee-Lee, Denis; Ross, Eric; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Clarke, Jean M.; Frimm, Annie M.

    2012-01-01

    ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (Cmax) and relative exposure for each dosing interval (AUCτ) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application. PMID:22777041

  18. Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers.

    PubMed

    Chinsangaram, Jarasvech; Honeychurch, Kady M; Tyavanagimatt, Shanthakumar R; Leeds, Janet M; Bolken, Tove' C; Jones, Kevin F; Jordan, Robert; Marbury, Thomas; Ruckle, Jon; Mee-Lee, Denis; Ross, Eric; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Clarke, Jean M; Frimm, Annie M; Hruby, Dennis E

    2012-09-01

    ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (C(max)) and relative exposure for each dosing interval (AUC(τ)) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.

  19. A pharmacokinetic and safety study of a fixed oral dose of enzastaurin HCl in native Chinese patients with refractory solid tumors and lymphoma

    PubMed Central

    Li, Su; Zhang, Weijing; Yang, Nong; Cui, Yimin; Huang, He; Cai, Ruiqing; Lin, Xiaoting; Fu, Xiaohong; Hong, Huangming; Lin, Tongyu

    2016-01-01

    Purpose This study was conducted to assess the pharmacokinetics and safety of enzastaurin in native Chinese patients with refractory solid tumors and lymphoma. Methods Eligible patients received 500 mg of enzastaurin orally once daily. The pharmacokinetics of enzastaurin and its metabolites were assessed on days 14 to 18. Patients were allowed to continue receiving the agent in a safety extension phase until disease progression or presentation with unacceptable toxicity. Results Twenty-five patients received at least 1 dose of enzastaurin, and twenty-one patients completed the pharmacokinetic phase. Fifteen patients entered the safety extension phase. Except for transient, asymptomatic grade 3 QT interval prolongation in one patient who had baseline grade 2 QT prolongation, other adverse events were of grade 1 to 2. The t1/2, Cav, ss, and AUCτ, ss for enzastaurin and its primary active metabolite LSN326020 were 14 and 42 h, 1,210 and 907 nmol/L, and 29,100 and 21,800 nmol•h/L, respectively. One patient with relapsed diffuse large B-cell lymphoma achieved a partial response that lasted for 8.1 months. Conclusions The pharmacokinetics of enzastaurin in Chinese cancer patients were consistent with those observed in previous studies abroad. Enzastaurin 500 mg daily was well tolerated by Chinese patients. We recommend 500 mg daily as the phase II dose in this population. Its efficacy in lymphoma deserves further investigation. Trial Registration ClinicalTrials.gov: NCT01432951 PMID:26942463

  20. Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products.

    PubMed

    Raney, Sam G; Franz, Thomas J; Lehman, Paul A; Lionberger, Robert; Chen, Mei-Ling

    2015-11-01

    The pharmacokinetic approach has accelerated the development of high-quality generic medicines with extraordinary cost savings, transforming the pharmaceutical industry and healthcare system in the USA. While this is true for systemically absorbed drug products, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. The current review explores the possibility of developing appropriate bioequivalence approaches based on pharmacokinetic principles for topical dermatological products. This review focuses on the strengths and limitations of the three most promising pharmacokinetics-based methods to evaluate the performance and bioequivalence of topical dermatological products, which include in vivo skin stripping, in vivo microdialysis, and in vitro permeation testing (IVPT) with excised human skin. It is hoped that recent advances in pharmaceutical and regulatory science will facilitate the development of robust bioequivalence approaches for these dosage forms, enable more efficient methodologies to compare the performance of new drug products in certain pre-approval or post-approval change situations, and promote the availability of high-quality generic versions of topical dermatological products.

  1. The effects of renal impairment on the pharmacokinetics, safety, and tolerability of naloxegol.

    PubMed

    Bui, Khanh; She, Fahua; Sostek, Mark

    2014-12-01

    The impact of renal impairment on the pharmacokinetics of a 25-mg oral dose of naloxegol was examined in patients with renal impairment classified as moderate, severe, or end-stage renal disease (ESRD) and compared with healthy subjects (n = 8/group). Geometric mean area under the plasma concentration-time curve (AUC) was increased in patients with moderate (1.7-fold) or severe (2.2-fold) impairment, and maximum plasma concentrations (Cmax ) were elevated in patients with moderate (1.1-fold) or severe (1.8-fold) impairment. These findings were driven by higher exposures in two patients in each of the moderate and severe impairment groups; exposures in all other patients were similar to the control group. Overall exposures in ESRD patients were similar and Cmax was 29% lower versus normal subjects. Renal impairment minimally affected other plasma pharmacokinetic parameters. As renal clearance was a minor component of total clearance, exposure to naloxegol was unaffected by the degree of renal impairment, with no correlation between either AUC or Cmax and estimated glomerular filtration rate (eGFR). Hemodialysis was an ineffective means to remove naloxegol. Naloxegol was generally well tolerated in all groups. Renal impairment could adversely affect clearance by hepatic and gut metabolism, resulting in the increased exposures observed in outliers of the moderate and severe renal impairment groups.

  2. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers.

    PubMed

    Spence, Rebecca; Mandagere, Arun; Dufton, Christopher; Venitz, Jürgen

    2008-12-01

    The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ET(A)-selective, propanoic acid-based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC(0-infinity)) and maximum plasma concentration (C(max)) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC(0-infinity) and C(max) for sildenafil and N-desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20-mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N-desmethyl sildenafil. Ambrisentan C(max) was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC(0-infinity) (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil C(max) was increased slightly (113.4% [99.6%-129.1%]), and AUC(0-infinity) was unchanged (98.7% [91.2%-110.5%]) with ambrisentan coadministration. N-desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.

  3. EVALUATION OF MULTIPLE PHARMACOKINETIC MODELING STRUCTURES FOR TRICHLOROETHYLENE

    EPA Science Inventory

    A series of PBPK models were developed for trichloroethylene (TCE) to evaluate biological processes that may affect the absorption, distribution, metabolism and excretion (ADME) of TCE and its metabolites.

  4. EVALUATION OF MULTIPLE PHARMACOKINETIC MODELING STRUCTURES FOR TRICHLOROETHYLENE

    EPA Science Inventory

    A series of PBPK models were developed for trichloroethylene (TCE) to evaluate biological processes that may affect the absorption, distribution, metabolism and excretion (ADME) of TCE and its metabolites.

  5. Safety Evaluation and Imaging Properties of Gadolinium-Based Nanoparticles in nonhuman primates

    PubMed Central

    Kotb, Shady; Piraquive, Joao; Lamberton, Franck; Lux, François; Verset, Michael; Di Cataldo, Vanessa; Contamin, Hugues; Tillement, Olivier; Canet-Soulas, Emmanuelle; Sancey, Lucie

    2016-01-01

    In this article, we report the safety evaluation of gadolinium-based nanoparticles in nonhuman primates (NHP) in the context of magnetic resonance imaging (MRI) studies in atherosclerosis bearing animals and healthy controls. In healthy NHP, the pharmacokinetics and toxicity profiles demonstrated the absence of dose, time, and sex-effects, as well as a suitable tolerance of intravenous administration of the nanoparticles. We investigated their imaging properties for arterial plaque imaging in a standard diet or a high cholesterol diet NHP, and compared their characteristics with clinically applied Gd-chelate. This preliminary investigation reports the efficient and safe imaging of atherosclerotic plaques. PMID:27725693

  6. Safety assured financial evaluation of maintenance

    NASA Astrophysics Data System (ADS)

    Erguina, Vera

    Management decisions in complex industrial facilities usually consider both the economic and environmental aspects of the plant's performance. For nuclear power plants (NPPs), safety is also a very substantial issue. The objectives of this dissertation are to develop and demonstrate a novel useful conceptual model that could be used to allocate maintenance funds for a nuclear power plant in such a way as to meet all specified safety requirements and objectives, while achieving a high degree of economic performance. The model is based on the general theory that the reliability of a plant at any time is a function of its initial reliability and the maintenance history of the individual plant components (Smith, 1997). Such a model can assist in evaluating strategic management decisions regarding allocation of funds for nuclear power plant maintenance. It could be used as a simulation tool; various scenarios could be studied to answer "what if" questions. Simulations of this type will allow a better understanding of the relationship between maintenance, economic performance, and safety, and consequently will lead to better decision making. The novelty of this model is tied to the intimate relationship that it develops between maintenance activities at a nuclear plant, and their relationship to prescribed safety requirements and to the economic performance of that plant.

  7. Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses

    PubMed Central

    Nagy, Christa F; Kumar, Dinesh; Perdomo, Carlos A; Wason, Suman; Cullen, Edward I; Pratt, Raymond D

    2004-01-01

    Aim This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination. Methods This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of ≥3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs). Results A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (<12%) but statistically significant (P = 0.02) increase in donepezil Cmax was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the tmax or AUC0–24 h of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported

  8. Intranasal Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users

    PubMed Central

    Cipriano, Alessandra; Colucci, Salvatore V.; Kapil, Ram P.; Geoffroy, Pierre; Hopyan, Talar; Levy-Cooperman, Naama

    2016-01-01

    Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. Design. Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods. During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. Results. Insufflation of both HYD coarse and fine particles led to lower “At this Moment” Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. Conclusions. HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder. PMID:26814240

  9. Preliminary safety, pharmacokinetics, and efficacy of regorafenib, cisplatin, and pemetrexed in patients with advanced non-squamous non-small cell lung cancers

    PubMed Central

    Hellmann, Matthew D; Sturm, Isrid; Trnkova, Zuzana Jirakova; Lettieri, John; Diefenbach, Konstanze; Rizvi, Naiyer A.; Gettinger, Scott N.

    2016-01-01

    Structured Abstract Purpose The addition of bevacizumab, an anti-angiogenesis agent, to cytotoxic chemotherapy improves survival in patients with advanced non-squamous non-small cell lung cancers (nsNSCLCs). Regorafenib is an oral multi-targeted kinase inhibitor with potent anti-angiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. This phase I trial evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. Methods Chemotherapy-naïve patients with advanced nsNSCLCs were treated with regorafenib 60mg/day continuously and cisplatin 75mg/m2 plus pemetrexed 500mg/m2 once every three weeks for up to six cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. Results Nine patients enrolled prior to premature termination of the study due to slow recruitment and a change in the development strategy of regorafenib by the study sponsor, partially due to slow enrollment. Five patients experienced at least one treatment-related Grade 3 adverse event. No grade 4–5 toxicity occurred. 5 of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range 1.5–15.1). Minor pharmacokinetic (PK) interactions between regorafenib and chemotherapy were observed. Conclusions Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naïve patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results. PMID:26003007

  10. Comparative pharmacokinetics and safety of a novel lyophilized amphotericin B lecithin-based oil-water microemulsion and amphotericin B deoxycholate in animal models.

    PubMed

    Brime, Begona; Frutos, Paloma; Bringas, Pilar; Nieto, Ana; Ballesteros, M Paloma; Frutos, Gloria

    2003-07-01

    Amphotericin B (AmB) has been a most effective systemic antifungal agent, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation Fungizone (D-AmB). To lower AmB-associated toxicity, AmB may be integrated into oil-in-water lecithin-based microemulsions. The present study compares the pharmacokinetic characteristics of D-AmB with the alternative formulation of AmB in microemulsion (M-AmB), which has proved effective in a murine candidiasis model. Both formulations were given by intravenous bolus: D-AmB 1 mg/kg, and M-AmB 0.5, 1 or 2 mg/kg. The pharmacokinetics of D-AmB and M-AmB have several differences, specifically with regard to the respective Cmax and AUC0- infinity values. Elimination of AmB from serum was biphasic for both M-AmB and D-AmB. Single-dose D-AmB (1 mg/kg) achieved a Cmax of 3.89 +/- 0.48 mg/L and an AUC0- infinity of 32.28 +/- 7.31 mg.h/L, whereas single-dose M-AmB (1 mg/kg) by comparison achieved a lower Cmax (2.92 +/- 0.54 mg/L) and a lower AUC0- infinity (21.89 +/- 5.17 mg.h/L). To evaluate the safety of M-AmB, a multiple-dose toxicity study was performed in groups of 10 mice, each receiving D-AmB 1 mg/kg, or M-AmB 1, 1.5, 2 or 3 mg/kg. The findings suggest that, in comparison with D-AmB, M-AmB produces no histologically demonstrable renal lesions, or changes in clinical chemistry.

  11. EVALUATING RISK IN OLDER ADULTS USING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS

    EPA Science Inventory

    The rapid growth in the number of older Americans has many implications for public health, including the need to better understand the risks posed by environmental exposures to older adults. An important element for evaluating risk is the understanding of the doses of environment...

  12. EVALUATING RISK IN OLDER ADULTS USING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS

    EPA Science Inventory

    The rapid growth in the number of older Americans has many implications for public health, including the need to better understand the risks posed by environmental exposures to older adults. An important element for evaluating risk is the understanding of the doses of environment...

  13. A probabilistic bridge safety evaluation against floods.

    PubMed

    Liao, Kuo-Wei; Muto, Yasunori; Chen, Wei-Lun; Wu, Bang-Ho

    2016-01-01

    To further capture the influences of uncertain factors on river bridge safety evaluation, a probabilistic approach is adopted. Because this is a systematic and nonlinear problem, MPP-based reliability analyses are not suitable. A sampling approach such as a Monte Carlo simulation (MCS) or importance sampling is often adopted. To enhance the efficiency of the sampling approach, this study utilizes Bayesian least squares support vector machines to construct a response surface followed by an MCS, providing a more precise safety index. Although there are several factors impacting the flood-resistant reliability of a bridge, previous experiences and studies show that the reliability of the bridge itself plays a key role. Thus, the goal of this study is to analyze the system reliability of a selected bridge that includes five limit states. The random variables considered here include the water surface elevation, water velocity, local scour depth, soil property and wind load. Because the first three variables are deeply affected by river hydraulics, a probabilistic HEC-RAS-based simulation is performed to capture the uncertainties in those random variables. The accuracy and variation of our solutions are confirmed by a direct MCS to ensure the applicability of the proposed approach. The results of a numerical example indicate that the proposed approach can efficiently provide an accurate bridge safety evaluation and maintain satisfactory variation.

  14. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.

    PubMed

    Stoch, S Aubrey; Zajic, Stefan; Stone, Julie A; Miller, Deborah L; van Bortel, Lucas; Lasseter, Kenneth C; Pramanik, Barnali; Cilissen, Caroline; Liu, Qi; Liu, Lida; Scott, Boyd B; Panebianco, Deborah; Ding, Yu; Gottesdiener, Keith; Wagner, John A

    2013-05-01

    To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction. Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing. © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. British Journal of

  15. Safety and Pharmacokinetics of an Intramuscular Monoclonal Antibody (SB 209763) against Respiratory Syncytial Virus (RSV) in Infants and Young Children at Risk for Severe RSV Disease

    PubMed Central

    Meissner, H. Cody; Groothuis, Jessie R.; Rodriguez, William J.; Welliver, Robert C.; Hogg, Geoff; Gray, Peter H.; Loh, Richard; Simoes, Eric A. F.; Sly, Peter; Miller, Ann K.; Nichols, Alice I.; Jorkasky, Diane K.; Everitt, Daniel E.; Thompson, Kathleen A.

    1999-01-01

    We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (≤35 weeks’ gestation) or exhibited bronchopulmonary dysplasia were administered either single or repeat (two doses, 8 weeks apart) intramuscular injections of SB 209763 at a concentration of 0.25, 1.25, 5.0, or 10.0 mg/kg or of a placebo. Four of 229 adverse events were considered related to the study drug, including purpura (n = 3) and thrombocytosis (n = 1). No subject developed a detectable level of anti-SB 209763 antibody. Approximately 1 week after administration of the second dose of SB 209763 at 10 mg/kg, the mean plasma concentration (n = 9) was 68.5 μg/ml. The terminal half-life (T1/2) determined by noncompartmental analysis ranged from 22 to 50 days. The population pharmacokinetics for SB 209763 following intramuscular administration was appropriately described by a one-compartment model with first-order input and elimination. Higher values for clearance and volume of distribution at steady state were observed for younger patients, with values decreasing to 0.143 (ml/h)/kg and 161 mL/kg, respectively, by a mean age of 298 days (∼10 months). The mean T1/2 of SB 209763 for the study population was 32.5 days. No other factor (dose, weight, gender, race, premature birth, or bronchopulmonary dysplasia) was observed to alter the population pharmacokinetics of SB 209763 in this study of infants and young children. The mean neutralization titer on day 6 was 286, and the mean fusion inhibition titer was 36. At least 57% of subjects dosed at 1.25 to 10.0 mg of SB 209763 per kg of body weight who were seronegative at baseline experienced a fourfold or greater increase in fusion inhibition titer. Nine RSV infections were documented

  16. Pharmacokinetic comparison and bioequivalence evaluation of losartan/ hydrochlorothiazide tablet between Asian Indian and Japanese volunteers.

    PubMed

    Kumar, Sudershan; Monif, Tausif; Khuroo, Arshad; Reyar, Simrit; Jain, Rakesh; Singla, Ajay K; Kurachi, Kazuya

    2014-01-01

    To demonstrate the bioequivalence between the test and reference formulations of losartan/hydrochlorothiazide 50 + 12.5 mg tablet and evaluate the effect of ethnicity on pharmacokinetics properties of losartan, losartan carboxylic acid and hydrochlorothiazide on healthy Asian Indian and Japanese volunteers. Randomized, open-label, crossover, bioavailability studies were conducted separately in healthy Asian Indian and Japanese volunteers. One tablet either of test or of reference product was administered after 10 hours of overnight fasting. After dosing, serial blood samples were collected for a period of 48 hours for both the studies. Plasma samples were analyzed for losartan, losartan carboxylic acid and hydrochlorothiazide by a validated liquid chromatographic and mass spectrometric method (LC-MS/MS). The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, tmax, and other pharmacokinetics parameters were determined from plasma concentration-time profiles for both test and reference formulations of losartan/hydrochlorothiazide 50 + 12.5 mg tablets. Statistical evaluations were done to evaluate bioequivalence between generic test formulation (EPR0001) and Japanese reference product (Preminent®). Losartan, losartan carboxylic acid and hydrochlorothiazide were well tolerated by subjects in all periods of each study under fasted conditions. No serious adverse events were observed. The ratios of least square means for AUC0-t and Cmax and the affiliated 90% confidence intervals were within acceptance range recommended by PMDA. Marginal differences were observed in pharmacokinetic values of Asian Indian and Japanese volunteers. The results of these bioavailability studies indicate that the test formulation of losartan/hydrochlorothiazide 50 + 12.5 mg (EPR0001) tablets is bioequivalent to marketed Preminent® reference formulation in Asian Indian and Japanese volunteers, when administered under fasting conditions. Both test and reference formulations were well tolerated

  17. Evaluation of the Pharmacokinetics and Efficacy of a Busulfan Test Dose in Adult Patients Undergoing Myeloablative Hematopoietic Cell Transplantation.

    PubMed

    Weil, Elizabeth; Zook, Felicia; Oxencis, Carolyn; Canadeo, Angela; Urmanski, Angela; Waggoner, Mindy; Eastwood, Daniel; Pasquini, Marcelo; Hamadani, Mehdi; Hari, Parameswaran

    2017-03-10

    Owing to interpatient variability in busulfan exposure, therapeutic monitoring of busulfan is often used in myeloablative allogeneic transplantation to ensure that patients are near the optimal steady-state goal of 900 ng/mL. One challenge in therapeutic monitoring of busulfan is the brief course of busulfan treatment, requiring prompt analysis and dose adjustments as needed. Pharmacokinetic evaluation of a busulfan test dose before the start of the conditioning regimen would allow for all conditioning regimen doses to be given at the calculated optimized dose. An observational study was completed to evaluate the effects of a busulfan test dose of .9 mg/kg administered before the start of a myeloablative intravenous busulfan-based conditioning regimen. Sixty adult patients who received a busulfan conditioning regimen were reviewed, including 30 patients who had not yet received the busulfan test dose (pretest dose group) and 30 patients who had received the busulfan test dose (posttest dose group). The primary objective was a pharmacokinetic evaluation of the percentage of patients who achieved the desired steady-state goal using the test dose strategy. The safety and efficacy of the busulfan test dose were evaluated as well. The average busulfan steady-state level after the first dose of the conditioning regimen was significantly lower in the pre-test dose group compared with the post-test dose group (660 ng/mL versus 879.9 ng/mL; P < .001). Compared with the post-test dose group, significantly fewer patients in the pre-test dose group were within 10% of the busulfan steady-state goal (10% versus 73.3%; P < .001) or within 5% of the goal (0% versus 53%; P < .001). Requirements for parenteral nutrition and/or patient-controlled analgesia owing to mucositis and veno-occlusive disease rates were not significantly different between the pre-test dose group and the post-test dose group. The rates of disease relapse, mortality, and acute graft

  18. Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers

    PubMed Central

    Tacca, Mario Del; Pasqualetti, Giuseppe; Gori, Giovanni; Pepe, Pasquale; Di Paolo, Antonello; Lastella, Marianna; De Negri, Ferdinando; Blandizzi, Corrado

    2013-01-01

    Purpose The primary aim of the present study was to assess the pharmacokinetic bioequivalence between a generic formulation of meloxicam 15 mg tablets (Meloxicam Hexal) and its respective brand product (Mobic), in order to verify whether the generic product conforms to the regulatory standards of bioequivalence in the postmarketing setting. As a secondary exploratory aim, the pharmacodynamic effects of the two formulations were also evaluated by means of rating scales following hyperalgesia induced by cutaneous freeze injury. Subjects and methods A single 15 mg dose of generic or branded meloxicam tablets was administered to 24 healthy male volunteers in a crossover fashion. Plasma samples, collected for 24 hours after dosing, were assayed for meloxicam concentration by a validated highperformance liquid chromatography method. Results The analysis of pharmacokinetic parameters did not show any significant difference between the two meloxicam formulations: the 90% confidence intervals fell within the acceptance range of 80%–125% (0.84–1.16 for area under the curve [0–24], and 0.89–1.23 for peak concentration). No difference in the pharmacodynamic end point was observed between the two groups. Conclusion The pharmacokinetic profiles of the two meloxicam formulations confirm the regulatory criteria for bioequivalence; pharmacodynamic data indicate a similar antihyperalgesic effect. The two formulations can be used interchangeably in the clinical setting. PMID:23901278

  19. Improved Safety, Bioavailability and Pharmacokinetics of Zidovudine through Lactoferrin Nanoparticles during Oral Administration in Rats.

    PubMed

    Kumar, Prashant; Lakshmi, Yeruva Samrajya; C, Bhaskar; Golla, Kishore; Kondapi, Anand K

    2015-01-01

    Zidovudine (AZT) is one of the most referred antiretroviral drug. In spite of its higher bioavailability (50-75%) the most important reason of its cessation are bone marrow suppression, anemia, neutropenia and various organs related toxicities. This study aims at the improvement of oral delivery of AZT through its encapsulation in lactoferrin nanoparticles (AZT-lactonano). The nanoparticles (NPs) are of 50-60 nm in size and exhibit 67% encapsulation of the AZT. They are stable in simulated gastric and intestinal fluids. Anti-HIV-1 activity of AZT remains unaltered in nanoformulation in acute infection. The bioavailability and tissue distribution of AZT is higher in blood followed by liver and kidney. AZT-lactonano causes the improvement of pharmacokinetic profile as compared to soluble AZT; a more than 4 fold increase in AUC and AUMC in male and female rats. The serum Cmax for AZT-lactonano was increased by 30%. Similarly there was nearly 2-fold increase in Tmax and t1/2. Our in vitro study confirms that, the endosomal pH is ideal for drug release from NPs and shows constant release from up to 96h. Bone marrow micronucleus assay show that nanoformulation exhibits approximately 2fold lower toxicity than soluble form. Histopathological and biochemical analysis further confirms that less or no significant organ toxicities when nanoparticles were used. AZT-lactonano has shown its higher efficacy, low organs related toxicities, improved pharmacokinetics parameter while keeping the antiviral activity intact. Thus, the nanoformulation are safe for the target specific drug delivery.

  20. Analgesics in Pregnancy: An Update on Use, Safety and Pharmacokinetic Changes in Drug Disposition.

    PubMed

    Price, Hayley R; Collier, Abby C

    2017-08-25

    Although medications should only be prescribed in pregnancy if benefits to the mother outweigh the risk to the fetus, drug use in pregnancy especially prescribed and over-the-counter analgesics, is very common. The objective of this review is to present an update on known changes in analgesic disposition in pregnancy caused by pharmacokinetic mechanisms. Herein, we discuss a wide range of medical, biomedical and scientific literature that includes reports from the fields of dentistry, general medicine, obstetrics and gynecology, pharmacology and toxicology to provide an update on the use (including indications, contraindications and concerns) of major classes of analgesics during human pregnancy. Over 50% of analgesics are in pregnancy category C, and even more category D specifically in the third trimester. Changes in renal filtration, cardiac output, plasma protein concentration and plasma volume particularly affect analgesics and dose adjustments may be necessary to maintain therapeutic concentrations in pregnant woman, and/or to protect the developing fetus. Analgesics are one of the most frequently used drug classes in pregnancy. More than 60% of women self-report using analgesics while pregnant, both prescribed and by self-medication. For the majority of analgesics available (excepting acetaminophen and the NSAIDs, and to a lesser extent certain opioids), good prospective clinical trials documenting pharmacokinetic changes do not exist. More research is needed in both the scientific and clinical community to understand the risks and benefits of analgesic use in pregnancy, particularly as prevalence is rising. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. [Elements of pharmacodynamics and pharmacokinetics].

    PubMed

    Piette, F; Soubrie, C

    1990-05-21

    A knowledge of pharmacokinetic data is particularly important with drugs that have a narrow margin of safety. Exhaustive pre-marketing pharmacokinetic investigations and pharmacokinetic studies in populations are the two principal means of acquiring such knowledge. Although popular, the concept of half-life which decreases with age for many drugs is insufficient to calculate dosage in elderly people. Measurements of creatinine clearance provide an almost mathematical approach to the dosage of drugs that are excreted exclusively by the kidneys. In contrast, changes in hepatic metabolism with age and pathology are difficult to evaluate, and their consequences are often vaguely perceived. Our knowledge of relationships between age and pharmacodynamics is still in infancy. Owing to the wide consumption of medicine by elderly people, drug interactions are frequent at all stages, including absorption, metabolization, transport and site of action.

  2. Moxifloxacin pharmacokinetic profile and efficacy evaluation in empiric treatment of community-acquired pneumonia.

    PubMed

    Öbrink-Hansen, Kristina; Hardlei, Tore Forsingdal; Brock, Birgitte; Jensen-Fangel, Søren; Kragh Thomsen, Marianne; Petersen, Eskild; Kreilgaard, Mads

    2015-04-01

    When antimicrobials are used empirically, pathogen MICs equal to clinical breakpoints or epidemiological cutoff values must be considered. This is to ensure that the most resistant pathogen subpopulation is appropriately targeted to prevent emergence of resistance. Accordingly, we determined the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic-pharmacodynamic (PK-PD) estimates are obtained. Moxifloxacin plasma concentrations were determined the day after therapy initiation using ultra-high-performance liquid chromatography. Peak drug concentrations (Cmax) and area under the free drug concentration-time curve from 0 to 24 h (fAUC0-24) values predicted for each patient were evaluated against epidemiological cutoff MIC values for Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila. PK-PD targets adopted were a Cmax/MIC of ≥12.2 for all pathogens, an fAUC0-24/MIC of >34 for S. pneumoniae, and an fAUC0-24/MIC of >75 for H. influenzae and L. pneumophila. Individual predicted estimates for Cmax/MIC and fAUC0-24/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable for S. pneumoniae and H. influenzae but not for L. pneumophila. These results indicate that caution must be taken when moxifloxacin is used as monotherapy to treat community-acquired pneumonia caused by L. pneumophila. In conclusion, this report reveals key information relevant to the empirical treatment of community-acquired pneumonia while highlighting the robust and flexible nature of this population pharmacokinetic model to predict therapeutic success. (Clinical Trials Registration no. NCT01983839.).

  3. Evaluation of a Pharmacokinetic Interaction between Telmisartan and Chlorthalidone in Healthy Male Adult Subjects.

    PubMed

    Seong, Sook Jin; Lim, Mi-Sun; Lee, Joomi; Ohk, Boram; Gwon, Mi-Ri; Kim, Bo Kyung; Kim, Hyun-Ju; Yang, Dong Heon; Lee, Hae Won; Kang, Woo Youl; Yoon, Young-Ran

    2016-08-01

    Combination therapy is recommended for the effective management of hypertension according to most treatment guidelines, including those of the US Joint National Committee. Therefore, pharmacokinetic drug interactions are an important issue in combination therapy for hypertension. In this study, the pharmacokinetic properties of telmisartan and chlorthalidone were evaluated to investigate their pharmacokinetic interactions in healthy subjects. Two separate, randomized, multiple-dose, two-period, one-sequence studies were conducted. In study A, 43 participants received 80 mg of telmisartan orally for 7 days, and were then administered oral chlorthalidone 25 mg for 14 days (days 8-21), coadministered with 80 mg of telmisartan from day 15. In study B, 14 participants received oral chlorthalidone (25 mg) for 13 days, followed by coadministration with 80 mg of telmisartan orally for 7 days. The geometric mean ratios (GMRs) (90 % confidence intervals [CIs]) of the maximum plasma concentration (C max,ss) and area under the concentration-time curve for the dosing interval at steady state (AUCτ,ss) of telmisartan (with and without chlorthalidone) were 1.018 (0.861-1.203) and 1.099 (1.015-1.190), respectively. For chlorthalidone (with/without telmisartan), the GMRs (90 % CIs) for C max,ss and AUCτ,ss were 0.996 (0.922-1.075) and 0.992 (0.925-1.064), respectively. The GMRs and 90 % CIs for telmisartan and chlorthalidone were all within the 0.80-1.25 range. Thus, in this study, there was no significant pharmacokinetic interaction between telmisartan and chlorthalidone. CLINICALTRIAL. NCT01806363.

  4. Safety, Pharmacokinetics, Pharmacodynamics, and Plasma Lipoprotein Distribution of Eritoran (E5564) during Continuous Intravenous Infusion into Healthy Volunteers

    PubMed Central

    Rossignol, Daniel P.; Wasan, Kishor M.; Choo, Eugene; Yau, Edwin; Wong, Nancy; Rose, Jeffrey; Moran, Jeffrey; Lynn, Melvyn

    2004-01-01

    Eritoran, a structural analogue of the lipid A portion of lipopolysaccharide (LPS), is an antagonist of LPS in animal and human endotoxemia models. Previous studies have shown that low doses (350 to 3,500 μg) of eritoran have demonstrated a long pharmacokinetic half-life but a short pharmacodynamic half-life. The present study describes the safety, pharmacokinetics and pharmacodynamics, and lipid distribution profile of eritoran during and after a 72-h intravenous infusion of 500, 2,000, or 3,500 μg/h into healthy volunteers. Except for the occurrence of phlebitis, eritoran administration over 72 h was safe and well tolerated. Eritoran demonstrated a slow plasma clearance (0.679 to 0.930 ml/h/kg of body weight), a small volume of distribution (45.6 to 49.8 ml/kg), and a relatively long half-life (50.4 to 62.7 h). In plasma, the majority (∼55%) of eritoran was bound to high-density lipoproteins. During infusion and for up to 72 h thereafter, ex vivo response of blood to 1- or 10-ng/ml LPS was inhibited by ≥85%, even when the lowest dose of eritoran (500 μg/h) was infused. Inhibition of response was dependent on eritoran dose and the concentration of LPS used as an agonist. Finally, in vitro analysis with purified lipoprotein and protein fractions from plasma obtained from healthy volunteers indicated that eritoran is inactivated by high-density but not low-density lipoproteins, very-low-density lipoproteins, or albumin. From these results, we conclude that up to 252 mg of eritoran can be safely infused into normal volunteers over 72 h and even though it associates extensively with high-density lipoproteins, antagonistic activity is maintained, even after infusion ceases. PMID:15328078

  5. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran.

    PubMed

    Glund, Stephan; Moschetti, Viktoria; Norris, Stephen; Stangier, Joachim; Schmohl, Michael; van Ryn, Joanne; Lang, Benjamin; Ramael, Steven; Reilly, Paul

    2015-05-01

    Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.

  6. Pharmacokinetics, Pharmacodynamics, Safety, and Clinical Activity of Multiple Doses of RCT-18 in Chinese Patients With Systemic Lupus Erythematosus.

    PubMed

    Zhao, Qian; Chen, Xia; Hou, Yong; Jiang, Ji; Zhong, Wen; Yao, Xuejing; Wang, Wenxiang; Li, Lin; Fang, Jianmin; Zhang, Fengchun; Hu, Pei

    2016-08-01

    RCT-18 is a novel recombinant fusion protein that blocks the activity of a B-lymphocyte stimulator and a proliferation-inducing ligand. This was a randomized, single-blind, and placebo-controlled phase 1 study in 12 patients with systemic lupus erythematosus. Eligible patients were randomized 3:1 to receive multiple subcutaneous doses of RCT-18 for 4 weeks (180 mg, once weekly) or placebo and monitored over an 84-day observation period for pharmacokinetics, pharmacodynamics, immunogenicity, safety, and clinical activity. After multiple-dose RCT-18, the maximal serum concentration (Cmax ) of total and free RCT-18 was reached within 1 to 2 days. Mean elimination half-life for total RCT-18 and free RCT-18 was 11.4 to 26.4 days and 2.4 to 26.5 days, respectively. Slight accumulation was found after multiple subcutaneous administrations. The average accumulation ratios of AUC and Cmax after the fourth administration of RCT-18 were 2.0 and 1.7 for total RCT-18, and 1.8 and 1.6 for free RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to Cmax of 14 to 46 days. Pharmacokinetic characteristics of RCT-18 in SLE patients were similar to those in patients with rheumatoid arthritis. No positive reaction was detected in the immunogenicity assessments. RCT-18 was biologically active, according to serum immunoglobulin and B-cell levels. Treatment-related IgM and IgA reduction was found during this study. CD19(+) , IgD(+) , and CD27(+) B-cell counts were increased after administration and decreased subsequently. SLE patients treated with RCT-18 were more prone to infections, including moderate and severe infections. Lower dosages of RCT-18 should be considered in further clinical development. © 2016, The American College of Clinical Pharmacology.

  7. Pharmacokinetics, Safety, and Tolerability of a New Fluticasone Propionate Multidose Dry Powder Inhaler Compared With Fluticasone Propionate Diskus(®) in Healthy Adults.

    PubMed

    Vutikullird, Apinya Bee; Gillespie, Michael; Song, Sharon; Steinfeld, Jonathan

    2016-04-01

    Fluticasone propionate (Fp) is an inhaled corticosteroid with well-established safety and efficacy profiles. This study evaluated the systemic pharmacokinetics of Fp inhaled from a novel, inhalation-driven multidose dry powder inhaler (MDPI) that does not require coordination of actuation with inhalation. This was a single-center, open-label, randomized, 3-period crossover, single-dose study in healthy Japanese and Caucasian subjects aged 20-45 years, inclusive. Subjects were randomized to one of six treatment sequences including combinations of four inhalations of Fp MDPI 100 μg (400 μg total dose), Fp MDPI 200 μg (800 μg total dose), and Fp Diskus(®) 100 μg (400 μg total dose). The primary objective was to assess pharmacokinetics (maximum plasma concentration [Cmax] and area under concentration-vs.-time curve [AUC]) for each treatment. Safety and tolerability were also assessed. Thirty subjects (15 Caucasian, 15 Japanese) met entry criteria and were randomized; all 30 subjects completed the study. At the inhaled Fp total doses evaluated (400 and 800 μg), the shapes of plasma concentration-vs.-time curves and systemic exposure (AUC0-t and Cmax) were similar in Japanese and Caucasian subjects. Geometric mean ratios (Japanese/Caucasian) for AUC0-t ranged from 1.11 to 1.15, and for Cmax ranged from 0.90 to 1.05, with no substantial differences between ethnic groups. In both ethnic groups, and in the combined population, systemic exposure (AUC0-t and Cmax) was highest for Fp MDPI 800 μg, followed by Fp MDPI 400 μg, and last by Fp Diskus 400 μg. No clinical laboratory, vital signs, or physical examination findings were considered clinically significant. Systemic exposure following inhaled single doses of Fp was comparable in healthy adult Japanese and Caucasian subjects for each total dose and inhaler. The new MDPI provided more efficient drug delivery than Diskus, suggesting that Fp MDPI may provide similar clinical efficacy at a lower

  8. Developing Methodologies for Evaluating the Earthquake Safety of Existing Buildings.

    ERIC Educational Resources Information Center

    Bresler, B.; And Others

    This report contains four papers written during an investigation of methods for evaluating the safety of existing school buildings under Research Applied to National Needs (RANN) grants. In "Evaluation of Earthquake Safety of Existing Buildings," by B. Bresler, preliminary ideas on the evaluation of the earthquake safety of existing…

  9. Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study.

    PubMed

    Quach, Hang; White, Darrell; Spencer, Andrew; Ho, P Joy; Bhutani, Divaya; White, Mike; Inamdar, Sandeep; Morris, Chris; Ou, Ying; Gyger, Martin

    2017-06-01

    The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m(2). This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m(2) in normal renal function and ESRD patients. Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m(2) (cycle 1 day 1-2), escalated to 27 mg/m(2) on cycle 1 day 8; if tolerated, 56 mg/m(2) starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively. 26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients. There were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure-response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.

  10. 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

    2017-06-16

    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

  11. Pegvisomant bioavailability of single 30 mg/mL subcutaneous injection compared to two 15 mg/mL subcutaneous injections: a pharmacokinetic, safety and tolerability study.

    PubMed

    Jen, Juif; LaBadie, Robert R; Liang, Yali; Crownover, Penelope H; Gao, Xiang; Hey-Hadavi, Juliana H

    2013-08-01

    The study was conducted to evaluate the pharmacokinetics (PK), relative bioavailability (relBA), safety and tolerability of two single-dose pegvisomant subcutaneous (SC) administrations: one injection of 30 mg/mL (1 × 30 mg/mL) versus two injections of two 15 mg/mL (2 × 15 mg/mL). This was a 2-period, single-dose, crossover study in 14 healthy male and female subjects. All subjects received both administrations during the two treatment periods separated by a two-week washout. Serum samples were collected intensively up to 360 h post injection and were assayed by a validated enzyme linked immunosorbent assay (ELISA) for pegvisomant. PK parameters including AUC and Cmax were derived by noncompartmental analyses. Mixed effects model was used to obtain bioavailability estimates. Safety and tolerability were assessed by clinical monitoring, including adverse events, laboratory assessments and injection site reactions. All subjects completed the study. The relBA of 1 × 30 mg/mL relative to 2 × 15 mg/mL was 123.89% with a 90% CI (112.91-135.93%). Adjusted for the difference in actual pegvisomant amounts in both formulations the dose-adjusted relBA reduced to 112.97% with a 90% CI (103.09-123.80%). Single injection with a higher drug concentration in injection solution might have a role in this 13% higher bioavailability for 1 × 30 mg/mL administration. Other PK parameters for the two administrations were comparable. No laboratory abnormalities, vital signs, ECG, or injection site reactions of clinical concern were observed in either treatment. Comparable BA, safety and tolerability of the new 30 mg/mL strength to the currently marketed 15 mg/mL strength were established in this study. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis.

    PubMed

    O'Brien, S H; Yee, D L; Lira, J; Goldenberg, N A; Young, G

    2015-09-01

    Direct thrombin inhibitors offer potential advantages over unfractionated heparin but have been poorly studied in children. To determine appropriate dosing of bivalirudin in children and adolescents and the relationship between activated partial thromboplastin time (APTT) and plasma bivalirudin concentration. The UNBLOCK (UtilizatioN of BivaLirudin On Clots in Kids) study was an open-label, single-arm, dose-finding, pharmacokinetic, safety and efficacy study of bivalirudin for the acute treatment of deep vein thrombosis (DVT) in children aged 6 months to 18 years. Drug initiation consisted of a bolus dose (0.125 mg kg(-1) ) followed by continuous infusion (0.125 mg kg h(-1) ). Dose adjustments were based on the APTT, targeting a range of 1.5-2.5 times each patient's baseline APTT. Safety was assessed by specific bleeding endpoints and efficacy by repeat imaging at 48-72 h and 25-35 days. Eighteen patients completed the study. Following the bolus dose and the initial infusion rate, most patients' APTT values were within the target range. The infusion rate bivalirudin correlated more closely with drug concentration than the APTT. At 48-72 h, nine (50%) patients had complete or partial thrombus resolution, increasing to 16 (89%) at 25-35 days. No major and one minor bleeding event occurred. Bivalirudin demonstrated reassuring safety and noteworthy efficacy in terms of early clot resolution in children and adolescents with DVT. Although a widely available and familiar monitoring tool, the APTT correlates poorly with plasma bivalirudin concentration, possibly limiting its utility in managing pediatric patients receiving bivalirudin for DVT. © 2015 International Society on Thrombosis and Haemostasis.

  13. Safety Evaluation of Cannon and Recoilless Weapons

    DTIC Science & Technology

    1977-07-12

    34. REPORT NUMDER 2. GOVT ACCESSION NO. 3. RIECIPIEIT’S CATALOG NUM TdP-3-2-8051 Ř. TITLE (and Subtia.) T".YPE OF REPORT G Pf.,o1• •l U. S . AMY...TEST AND EVALUA _.---.- ’ P_ E TIONS PROC ’SAFETY .EVALUATION OF FinaL -* .ANON AND .,-OILLESS - APONS, 6. PERFORMING ORG. REPORT NUMBER 7. AUTHOR( s ) ’I...CONTRACT OR GRIANT NUMBER( s ) 9. PERFORMING ORGANIZATION NAME AND AODRESS 10. PROGRAM! ._L-MNT. PROJECT. TASK U. S . ARMY ABERDEEN PROVING GROUND

  14. Safety evaluation for packaging (onsite) SERF cask

    SciTech Connect

    Edwards, W.S.

    1997-10-24

    This safety evaluation for packaging (SEP) documents the ability of the Special Environmental Radiometallurgy Facility (SERF) Cask to meet the requirements of WHC-CM-2-14, Hazardous Material Packaging and Shipping, for transfer of Type B quantities (up to highway route controlled quantities) of radioactive material within the 300 Area of the Hanford Site. This document shall be used to ensure that loading, tie down, transport, and unloading of the SERF Cask are performed in accordance with WHC-CM-2-14. This SEP is valid until October 1, 1999. After this date, an update or upgrade to this document is required.

  15. [Clinical and pharmacokinetic evaluation of ceftazidime in children].

    PubMed

    Fujita, K; Sakata, H; Murono, K; Yoshioka, H; Maruyama, S; Sanae, N; Takimoto, M

    1984-03-01

    Forty-two pediatric patients were treated with ceftazidime ( CAZ ) in the doses ranging from 45.6 to 120 mg/kg/day for 2 to 10 days, and the clinical efficacy and side effects were evaluated. Among the 37 children with bacterial infections including pneumonia, bronchitis, tonsillitis, croup, cervical lymphadenitis, abdominal abscess and urinary tract infections, the results were excellent in 22, good in 12, fair in 2, and poor in 1 patient with pneumonia. Out of the 42 patients, 5 cases showed eosinophilia, but no clinical sign such as rash, fever or diarrhea, attributable to CAZ was observed during the study. The serum concentrations of CAZ in 4 patients ranged from 60.8 to 71.0 micrograms/ml (mean 66.1 micrograms/ml) at 30 minutes and from 0.5 to 1.2 micrograms/ml (mean 0.8 micrograms/ml) at 8 hours after 20 mg/kg intravenous bolus injection of the antibiotic. The mean serum half-life was 1.42 hours (85 minutes). Patients with impairment of renal function were excluded from this study.

  16. Safety and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-Binding Antibody VIS410 Support Treatment and Prophylaxis Based on Population Modeling of Seasonal Influenza A Outbreaks

    PubMed Central

    Wollacott, Andrew M.; Boni, Maciej F.; Szretter, Kristy J.; Sloan, Susan E.; Yousofshahi, Mona; Viswanathan, Karthik; Bedard, Sylvain; Hay, Catherine A.; Smith, Patrick F.; Shriver, Zachary; Trevejo, Jose M.

    2016-01-01

    Background Seasonal influenza is a major public health concern in vulnerable populations. Here we investigated the safety, tolerability, and pharmacokinetics of a broadly neutralizing monoclonal antibody (VIS410) against Influenza A in a Phase 1 clinical trial. Based on these results and preclinical data, we implemented a mathematical modeling approach to investigate whether VIS410 could be used prophylactically to lessen the burden of a seasonal influenza epidemic and to protect at-risk groups from associated complications. Methods Using a single-ascending dose study (n = 41) at dose levels from 2 mg/kg–50 mg/kg we evaluated the safety as well as the serum and upper respiratory pharmacokinetics of a broadly-neutralizing antibody (VIS410) against influenza A (ClinicalTrials.gov identifier NCT02045472). Our primary endpoints were safety and tolerability of VIS410 compared to placebo. We developed an epidemic microsimulation model testing the ability of VIS410 to mitigate attack rates and severe disease in at risk-populations. Findings VIS410 was found to be generally safe and well-tolerated at all dose levels, from 2–50 mg/kg. Overall, 27 of 41 subjects (65.9%) reported a total of 67 treatment emergent adverse events (TEAEs). TEAEs were reported by 20 of 30 subjects (66.7%) who received VIS410 and by 7 of 11 subjects (63.6%) who received placebo. 14 of 16 TEAEs related to study drug were considered mild (Grade 1) and 2 were moderate (Grade 2). Two subjects (1 subject who received 30 mg/kg VIS410 and 1 subject who received placebo) experienced serious AEs (Grade 3 or 4 TEAEs) that were not related to study drug. VIS410 exposure was approximately dose-proportional with a mean half-life of 12.9 days. Mean VIS410 Cmax levels in the upper respiratory tract were 20.0 and 25.3 μg/ml at the 30 mg/kg and 50 mg/kg doses, respectively, with corresponding serum Cmax levels of 980.5 and 1316 μg/mL. Using these pharmacokinetic data, a microsimulation model showed

  17. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.

    PubMed

    Dooley, K E; Bliven-Sizemore, E E; Weiner, M; Lu, Y; Nuermberger, E L; Hubbard, W C; Fuchs, E J; Melia, M T; Burman, W J; Dorman, S E

    2012-05-01

    Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

  18. Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers

    PubMed Central

    Dooley, KE; Bliven-Sizemore, EE; Weiner, M; Lu, Y; Nuermberger, EL; Hubbard, WC; Fuchs, EJ; Melia, MT; Burman, WJ; Dorman, SE

    2013-01-01

    Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AUC0–24) and maximum concentration (Cmax) were similar in the 15- and 20-mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time-dependent, accumulation occurred with daily dosing. The mean AUC0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01). Changes in the oral clearance of MDZ did not vary by RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose-proportional, and its CYP3A induction was robust. PMID:22472995

  19. Effectiveness, safety, and pharmacokinetics of quetiapine in aggressive children with conduct disorder.

    PubMed

    Findling, Robert L; Reed, Michael D; O'Riordan, Mary Ann; Demeter, Christine A; Stansbrey, Robert J; McNamara, Nora K

    2006-07-01

    To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale (RAAPPS), Nisonger Child Behavior Rating Form (NCBRF), and the Conners Parent Rating Scale (CPRS-48). Blood sampling for PK analyses occurred at the end of weeks 2 and 8. Seventeen children (16 boys, mean age 8.9 years) were treated. The mean dose at week 8 was 4.4 mg/kg (SD = 1.1 mg/kg). Significant decreases in the baseline scores of the RAAPPS, and several subscales of the NCBRF and the CPRS were found by the end of the study (p <.05). No patients discontinued because of an adverse event. No patients experienced extrapyramidal side effects. Quetiapine disposition was linear over the dose range studied. The elimination half-life of the drug averaged 3.9 and 2.9 hours and total body clearance averaged 3.5 and 3.0 L/hr/kg after study weeks 2 and 8, respectively. These preliminary data suggest that aggressive children with CD may benefit from quetiapine. The PK of quetiapine supports twice-daily dosing in children with CD.

  20. Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection.

    PubMed

    Trachtman, H; Frymoyer, A; Lewandowski, A; Greenbaum, L A; Feig, D I; Gipson, D S; Warady, B A; Goebel, J W; Schwartz, G J; Lewis, K; Anand, R; Patel, U D

    2015-07-01

    Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations. © 2015 American Society for Clinical Pharmacology and Therapeutics.

  1. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics.

    PubMed

    Ocean, Allyson J; Starodub, Alexander N; Bardia, Aditya; Vahdat, Linda T; Isakoff, Steven J; Guarino, Michael; Messersmith, Wells A; Picozzi, Vincent J; Mayer, Ingrid A; Wegener, William A; Maliakal, Pius; Govindan, Serengulam V; Sharkey, Robert M; Goldenberg, David M

    2017-10-01

    Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response. Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future

  2. Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

    PubMed Central

    Yu, Xiang-Qing; Robbie, Gabriel J.; Wu, Yuling; Esser, Mark T.; Jensen, Kathryn; Schwartz, Howard I.; Bellamy, Terramika; Hernandez-Illas, Martha

    2016-01-01

    ABSTRACT MEDI4893 is an investigational immunoglobulin G1(κ) monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple-amino-acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti-alpha-toxin-neutralizing activity, and antidrug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18 to 65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. The MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/ml (225-mg dose) to 1,784 μg/ml (5,000-mg dose). The area under the concentration-time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg · day/ml (225-mg dose) to 91,493 μg · day/ml (5,000-mg dose), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated to be 80 to 112 days, which is approximately 4-fold longer than the half-lives of other human immunoglobulin G antibodies. The alpha-toxin-neutralizing activity in serum correlated highly with the MEDI4893 concentrations in serum. Three adults transiently tested positive for ADA on day 151, but this did not have an impact on MEDI4893 serum concentrations or the MEDI4893 safety profile; no subjects exhibited serum ADA at the study end. These data support the continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia. (This study has been registered at ClinicalTrials.gov under identifier NCT02296320.) PMID:27795368

  3. Comparison of pharmacokinetics and safety of pegfilgrastim administered by two delivery methods: on-body injector and manual injection with a prefilled syringe.

    PubMed

    Yang, Bing-Bing; Morrow, Phuong Khanh; Wu, Xikun; Moxness, Michael; Padhi, Desmond

    2015-06-01

    For patients with clinically significant risk of febrile neutropenia, pegfilgrastim administration should occur the day after myelosuppressive chemotherapy; however, a variety of factors may preclude patients from returning to the clinic the next day for pegfilgrastim administration, necessitating other strategies. This study compared the pharmacokinetics and safety of pegfilgrastim administered via an on-body injector applied to the subject's skin versus manual injection using a prefilled syringe. Healthy subjects aged 18-50 years were randomized 1:1 to receive a single 6-mg subcutaneous pegfilgrastim dose from an on-body injector or a prefilled syringe. Blood for pharmacokinetic measurements was collected at baseline and prespecified time points after pegfilgrastim administration; safety was assessed throughout the 6-week study. Primary endpoints were maximum concentration (C max) and area under the concentration curve from time 0 to infinity (AUC0-inf). Secondary endpoints included safety, tolerability, and immunogenicity. Pegfilgrastim mean AUC0-inf values for the on-body injector (n = 125) and manual injection (n = 128) were 10,900 and 11,100 h ng/mL, respectively; mean C max values were 248 and 262 ng/mL, respectively. The least squares geometric mean ratios were 0.97 for C max and 1.00 for AUC0-inf; the corresponding 90 % CIs were within the prespecified range (0.80-1.25), indicating comparable pegfilgrastim pharmacokinetics between delivery methods. Treatment-emergent adverse events (AEs) were similar between groups (injector, 86 %; manual, 85 %). Injector- or syringe-related AEs were more prevalent with the injector (13 %; manual, 4 %); none were serious. No pegfilgrastim-neutralizing antibodies were detected. Pegfilgrastim pharmacokinetics and safety were comparable between the on-body injector and manual injection groups.

  4. Safety and Biosimilarity of ior(®)LeukoCIM Compared to Neupogen(®) Based on Toxicity, Pharmacodynamic, and Pharmacokinetic Studies in the Sprague-Dawley Rat.

    PubMed

    Licollari, Albert; Riddle, Katherine; Taylor, Simon R; Ledon, Nuris; Bolger, Gordon T

    2017-02-24

    This study examined the safety, pharmacodynamic and pharmacokinetic similarity of the human recombinant filgrastim products ior(®)LeukoCIM and Neupogen(®) following a 28-day repeated subcutaneous dose administration in male and female Sprague-Dawley rats with a 14-day recovery period. Safety profiling was based on clinical observations, clinical pathology, and pathology findings for control rats dosed with vehicle and rats dosed either with 15, 75, and 150 μg/kg of ior(®)LeukoCIM or with 150 μg/kg of Neupogen(®). The major adverse treatment-related clinical finding was mild to severe swelling of the hock-joint (tarsal joint) and hind limb, alone or accompanied with lameness which was more prominent in males and which had a similar frequency of occurrence for both ior(®)LeukoCIM and Neupogen(®). All adverse findings were fully reversible. As expected, ior(®)LeukoCIM and Neupogen(®) both increased white blood cell and neutrophil levels in rats and to a similar extent for high-dose ior(®)LeukoCIM and Neupogen(®). The pharmacokinetics of filgrastim following dosing with ior(®)LeukoCIM were well behaved and comparable for high-dose ior(®)LeukoCIM and Neupogen(®). The results of this study imply that ior(®)LeukoCIM and Neupogen(®) had similar safety profiles, pharmacodynamic responses, and pharmacokinetic profiles that suggest they are biosimilar.

  5. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis

    PubMed Central

    Yoo, Dae Hyun; Suh, Chang-Hee; Shim, Seung Cheol; Jeka, Slawomir; Cons-Molina, Francisco Fidencio; Hrycaj, Pawel; Wiland, Piotr; Lee, Eun Young; Medina-Rodriguez, Francisco G; Shesternya, Pavel; Radominski, Sebastiao; Stanislav, Marina; Kovalenko, Volodymyr; Sheen, Dong Hyuk; Myasoutova, Leysan; Lim, Mie Jin; Choe, Jung-Yoon; Lee, Sang Joon; Lee, Sung Young; Kwon, Taek Sang; Park, Won

    2017-01-01

    Objective To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents. Methods In this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration–time curve from time zero to last quantifiable concentration (AUC0–last) and maximum serum concentration after second infusion (Cmax). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24. Results 103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%–125% (AUC0–last: 97.7% (90% CI 89.2% to 107.0%); Cmax: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles. Conclusions CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety. Trial registration number NCT01534884. PMID:27624791

  6. A Pharmacokinetics, Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 Years.

    PubMed

    Scala, Mario; Koob, Meriam; de Buttet, Sophie; Bourrinet, Philippe; Felices, Mathieu; Jurkiewicz, Elzbieta

    2017-09-12

    The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety. This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization. Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2β) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 μmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2

  7. Pharmacokinetic and pharmacodynamic evaluation according to absorption differences in three formulations of ibuprofen.

    PubMed

    Shin, Dongseong; Lee, Sook Joung; Ha, Yu-Mi; Choi, Young-Sim; Kim, Jae-Won; Park, Se-Rin; Park, Min Kyu

    2017-01-01

    Prostaglandin E2 (PGE2) synthesis is modulated by COX2. Changes in PGE2 could be used to quantify the COX2 inhibition after ibuprofen administration. This study investigated the pharmacokinetic and pharmacodynamic relationships for COX2 inhibition according to three formulations of ibuprofen in healthy male subjects. A randomized, open-label, single-dose, three-treatment, six-sequence crossover study was performed in 36 healthy South Korean male volunteers. Enrolled subjects received the following three 200 mg ibuprofen formulations: ibuprofen arginine, solubilized ibuprofen capsule, and standard ibuprofen. Pharmacokinetic and pharmacodynamic blood samples were collected for 16 hours following treatment. For pharmacodynamic evaluations, lipopolysaccharide (LPS)-induced PGE2 inhibition at each time point compared to predose was measured. Noncompartmental analysis was used for pharmacokinetic assessment, and time-weighted average inhibition (WAI) of PGE2 was applied to the pharmacodynamic evaluation. After a single oral dose of the ibuprofen formulations, the median times to maximum concentration were 0.42, 0.5, and 1.25 hours in ibuprofen arginine, solubilized ibuprofen capsule, and ibuprofen, respectively. The maximum observed plasma concentration was lower in ibuprofen, and the area under the plasma concentration-time curve was comparable among the three formulations. A significant difference was observed between fast-acting formulations and standard ibuprofen tablets for both maximum concentration and time taken to reach it. Individual formulations had an effect on PGE2 WAI during the 8 hours following treatment, resulting in significantly lower WAI in standard ibuprofen: ibuprofen arginine 18.4%, solubilized ibuprofen capsule 18.4%, and standard ibuprofen 11.6%. Rapid absorption and higher peak concentration were observed in ibuprofen arginine and the solubilized ibuprofen capsule. Additionally, fast-acting formulations had more predominant inhibitory activity

  8. Pharmacokinetic and pharmacodynamic evaluation according to absorption differences in three formulations of ibuprofen

    PubMed Central

    Shin, Dongseong; Lee, Sook Joung; Ha, Yu-Mi; Choi, Young-Sim; Kim, Jae-Won; Park, Se-Rin; Park, Min Kyu

    2017-01-01

    Objective Prostaglandin E2 (PGE2) synthesis is modulated by COX2. Changes in PGE2 could be used to quantify the COX2 inhibition after ibuprofen administration. This study investigated the pharmacokinetic and pharmacodynamic relationships for COX2 inhibition according to three formulations of ibuprofen in healthy male subjects. Materials and methods A randomized, open-label, single-dose, three-treatment, six-sequence crossover study was performed in 36 healthy South Korean male volunteers. Enrolled subjects received the following three 200 mg ibuprofen formulations: ibuprofen arginine, solubilized ibuprofen capsule, and standard ibuprofen. Pharmacokinetic and pharmacodynamic blood samples were collected for 16 hours following treatment. For pharmacodynamic evaluations, lipopolysaccharide (LPS)-induced PGE2 inhibition at each time point compared to predose was measured. Noncompartmental analysis was used for pharmacokinetic assessment, and time-weighted average inhibition (WAI) of PGE2 was applied to the pharmacodynamic evaluation. Results After a single oral dose of the ibuprofen formulations, the median times to maximum concentration were 0.42, 0.5, and 1.25 hours in ibuprofen arginine, solubilized ibuprofen capsule, and ibuprofen, respectively. The maximum observed plasma concentration was lower in ibuprofen, and the area under the plasma concentration–time curve was comparable among the three formulations. A significant difference was observed between fast-acting formulations and standard ibuprofen tablets for both maximum concentration and time taken to reach it. Individual formulations had an effect on PGE2 WAI during the 8 hours following treatment, resulting in significantly lower WAI in standard ibuprofen: ibuprofen arginine 18.4%, solubilized ibuprofen capsule 18.4%, and standard ibuprofen 11.6%. Conclusion Rapid absorption and higher peak concentration were observed in ibuprofen arginine and the solubilized ibuprofen capsule. Additionally, fast

  9. Safety, efficacy and population pharmacokinetics of fixed-dose combination of artesunate-mefloquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in India.

    PubMed

    Valecha, Neena; Srivastava, Bina; Dubhashi, N G; Rao, B H Krishnamoorthy; Kumar, Ashwani; Ghosh, S K; Singh, Jai Prakash Narayan; Kiechel, J R; Sharma, Bhawna; Jullien, V; Dash, A P; Taylor, W R J; Anvikar, Anupkumar R

    2013-12-01

    India has switched over to artemisinin-based combination therapy (ACT) for the treatment of acute uncomplicated Plasmodium falciparum malaria and the ACT used in the national programme is artesunate + sulphadoxine-pyrimethamine. Since the efficacy of ACT is dependent also on the partner drug, there is a need to evaluate and deploy multiple ACTs. This multicentre, single-arm, open-label clinical trial was carried out to assess the efficacy, safety and population pharmacokinetics of a fixed dose combination (FDC) artesunate mefloquine (ASMQ) in P. falciparum infected, Indian adults at Panjim, Goa, and Mangalore, Karnataka between December 2007 and November 2008. A total of 77 patients (males 74) were screened and enrolled: 42 at Goa and 35 at Mangalore with a median age of 25 yr (range 18-55 yr). One patient failed in treatment on D53, a PCR proven new infection, seven developed recurrent vivax parasitaemia and 11 did not have a parasitological endpoint. By per protocol analysis, the D63 cure rate was 58/59 (98.3; 95% C.I. 90.9-99.9%), and 58/58, with PCR correction. ASMQ was well-tolerated and no serious adverse events were reported. The study showed that the ASMQ FDC was efficacious and well-tolerated for the treatment of acute, uncomplicated P. falciparum malaria in highly endemic, chloroquine resistant areas of Goa and Mangalore. It is a viable option for India.

  10. A Multicenter, Randomized, Open-Label, Pharmacokinetics and Safety Study of Pantoprazole Tablets in Children and Adolescents Aged 6 Through 16 Years With GERD

    PubMed Central

    Ward, Robert M.; Kearns, Gregory L.; Tammara, Brinda; Bishop, Phyllis; O’Gorman, Molly A.; James, Laura P.; Katz, Mitchell H.; Maguire, Mary K.; Rath, Natalie; Meng, Xu; Comer, Gail M.

    2011-01-01

    SUMMARY Children with GERD may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug’s kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged ≥6 through 11 years (study 1) and 12 through 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose, and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar toPK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults. PMID:20852004

  11. Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.

    PubMed

    Hara, Katsutoshi; Takahashi, Naoki; Wakamatsu, Akira; Caltabiano, Stephen

    2015-12-01

    This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3-1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  12. Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects.

    PubMed

    Cohen-Barak, Orit; Wildeman, Jacqueline; van de Wetering, Jeroen; Hettinga, Judith; Schuilenga-Hut, Petra; Gross, Aviva; Clark, Shane; Bassan, Merav; Gilgun-Sherki, Yossi; Mendzelevski, Boaz; Spiegelstein, Ofer

    2015-05-01

    Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43-77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with preclinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose-dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel ) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate-corrected QTcF interval. TV-1380, therefore, offers a safe once-weekly therapy to increase cocaine hydrolysis. © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  13. Safety, tolerability, and pharmacokinetics of 6-month daily dosing of an oral formulation of cyclosporine (ATOPICA for cats®) in cats

    PubMed Central

    Roberts, E S; VanLare, K A; Strehlau, G; Peyrou, M; Roycroft, L M; King, S

    2014-01-01

    Cyclosporine was proven efficacious in the treatment of feline hypersensitivity dermatitis. This target animal study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ATOPICA for Cats® (cyclosporine oral solution, USP) MODIFIED following 6-month daily dosing in cats. Forty healthy cats (four cats/sex/group) received 0, 8 (1×), 16 (2×), 24 (3×), or 40 (5×) mg/kg cyclosporine once daily for 6 months (183 days). Body weight, food consumption, ophthalmoscopic, physical examinations including neurological assessments, blood pressure, electrocardiography, clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), organ weights, and macroscopic and microscopic examinations were performed and assessed. In addition, blood concentrations of cyclosporine were measured at the pretreatment trough on Days 1, 2, 7, 14, 31, 91, 154, and 182, and post-treatment on Days 1, 31, and 182. Adverse effects possibly related to treatment included prolonged APTT and one report each of bone marrow hypocellularity and lymphoma; all occurred in cats treated with doses more than 16 mg/kg. There was no significant accumulation of cyclosporine beyond the first week of treatment. Results confirm that ATOPICA for Cats is safe and well tolerated in cats without unexpected accumulation beyond the first week of treatment when administered as directed. PMID:24134659

  14. Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects

    PubMed Central

    Cohen-Barak, Orit; Wildeman, Jacqueline; van de Wetering, Jeroen; Hettinga, Judith; Schuilenga-Hut, Petra; Gross, Aviva; Clark, Shane; Bassan, Merav; Gilgun-Sherki, Yossi; Mendzelevski, Boaz; Spiegelstein, Ofer

    2015-01-01

    Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43–77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with preclinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose-dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate-corrected QTcF interval. TV-1380, therefore, offers a safe once-weekly therapy to increase cocaine hydrolysis. PMID:25524052

  15. Safety, tolerability, and pharmacokinetics of 6-month daily dosing of an oral formulation of cyclosporine (ATOPICA for cats®) in cats.

    PubMed

    Roberts, E S; Vanlare, K A; Strehlau, G; Peyrou, M; Roycroft, L M; King, S

    2014-04-01

    Cyclosporine was proven efficacious in the treatment of feline hypersensitivity dermatitis. This target animal study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ATOPICA for Cats® (cyclosporine oral solution, USP) MODIFIED following 6-month daily dosing in cats. Forty healthy cats (four cats/sex/group) received 0, 8 (1×), 16 (2×), 24 (3×), or 40 (5×) mg/kg cyclosporine once daily for 6 months (183 days). Body weight, food consumption, ophthalmoscopic, physical examinations including neurological assessments, blood pressure, electrocardiography, clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), organ weights, and macroscopic and microscopic examinations were performed and assessed. In addition, blood concentrations of cyclosporine were measured at the pretreatment trough on Days 1, 2, 7, 14, 31, 91, 154, and 182, and post-treatment on Days 1, 31, and 182. Adverse effects possibly related to treatment included prolonged APTT and one report each of bone marrow hypocellularity and lymphoma; all occurred in cats treated with doses more than 16 mg/kg. There was no significant accumulation of cyclosporine beyond the first week of treatment. Results confirm that ATOPICA for Cats is safe and well tolerated in cats without unexpected accumulation beyond the first week of treatment when administered as directed.

  16. Efficacy, safety, pharmacokinetics and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: A phase II study

    PubMed Central

    Zhu, Andrew X.; Ancukiewicz, Marek; Supko, Jeffrey G.; Sahani, Dushyant V.; Blaszkowsky, Lawrence S.; Meyerhardt, Jeffrey A.; Abrams, Thomas A.; McCleary, Nadine Jackson; Bhargava, Pankaj; Muzikansky, Alona; Sheehan, Susan; Regan, Eileen; Vasudev, Eamala; Knowles, Michelle; Fuchs, Charles S.; Ryan, David P.; Jain, Rakesh K.; Duda, Dan G.

    2013-01-01

    Purpose We performed a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK) and biomarkers for cediranib. Results Cediranib treatment resulted in an estimated 3-month-PFS rate of 77% [60%, 99%]. Median PFS was 5.3 [3.5,9.7] months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 [7.5–13.6] months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%) and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX and CD34+CD133+CD45dim circulating progenitor cells and on-treatment levels of sVEGFR2. Conclusions Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not appear to affect the steady-state PK of cediranib. Exploratory studies suggested pro-angiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. PMID:23362324

  17. Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections.

    PubMed

    Wiederhold, Nathan P

    2016-01-01

    Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors. Because of this, many patients had subtherapeutic or undetectable posaconazole levels when the oral suspension was used. To overcome this limitation, a delayed-release tablet was developed and is now available for clinical use. Hot-melt extrusion technology is used to combine a pH-sensitive polymer with posaconazole to produce a formulation that releases the drug in the elevated pH of the intestine where absorption occurs rather than in the low-pH environment of the stomach. This results in enhanced bioavailability and increased posaconazole exposure. Studies in healthy volunteers have demonstrated significantly higher and more consistent exposures with the tablet formulation compared to the oral suspension. In addition, pharmacokinetic parameters following administration of the tablets were not significantly affected by medications that raise gastric pH or increase gastric motility, and the tablets could also be administered without regard to food. Similar results have also been found in patients at high risk for invasive fungal infections who have received posaconazole tablets. The tablet formulation also appears to be well tolerated to date, although data regarding clinical efficacy are needed.

  18. Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections

    PubMed Central

    Wiederhold, Nathan P

    2016-01-01

    Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors. Because of this, many patients had subtherapeutic or undetectable posaconazole levels when the oral suspension was used. To overcome this limitation, a delayed-release tablet was developed and is now available for clinical use. Hot-melt extrusion technology is used to combine a pH-sensitive polymer with posaconazole to produce a formulation that releases the drug in the elevated pH of the intestine where absorption occurs rather than in the low-pH environment of the stomach. This results in enhanced bioavailability and increased posaconazole exposure. Studies in healthy volunteers have demonstrated significantly higher and more consistent exposures with the tablet formulation compared to the oral suspension. In addition, pharmacokinetic parameters following administration of the tablets were not significantly affected by medications that raise gastric pH or increase gastric motility, and the tablets could also be administered without regard to food. Similar results have also been found in patients at high risk for invasive fungal infections who have received posaconazole tablets. The tablet formulation also appears to be well tolerated to date, although data regarding clinical efficacy are needed. PMID:26730212

  19. Self-micellizing solid dispersion of cyclosporine A for pulmonary delivery: Physicochemical, pharmacokinetic and safety assessments.

    PubMed

    Suzuki, Hiroki; Ueno, Kodai; Mizumoto, Takahiro; Seto, Yoshiki; Sato, Hideyuki; Onoue, Satomi

    2017-01-01

    The present study aimed to develop an inhalable self-micellizing solid dispersion of cyclosporine A (SMSD/CsA) for the direct delivery to the respiratory system with improved therapeutic efficacy and minimized systemic exposure. SMSD/CsA was obtained by wet-milling, and then jet-milled SMSD/CsA was blended with lactose carrier, producing a respirable powder of SMSD/CsA (SMSD/CsA-RP). The physicochemical, pharmacological, and pharmacokinetic properties of SMSD/CsA-RP were characterized, and the hepatotoxic and nephrotoxic potentials were investigated by biomarker analysis. Cascade impactor analysis demonstrated that SMSD/CsA-RP had high in vitro inhalation performance, with a fine particle fraction of 36%. In simulated lung fluid, the SMSD/CsA exhibited better dissolution behavior than amorphous CsA. Pretreatment with SMSD/CsA-RP resulted in significant suppression of antigen-evoked inflammatory events in rats. After intratracheal administration of SMSD/CsA-RP at a pharmacologically effective dose (100μg-CsA/rat), the AUC0-24 value was <1% of that after oral administration of Neoral(®) at a toxic dose (10mg-CsA/kg). Compared with oral Neoral(®), insufflated SMSD/CsA-RP showed 99% reductions of CsA concentrations in both liver and kidney. No significant increases of biomarker levels in plasma were observed even after repeated intratracheal administration of SMSD/CsA-RP for 7days. From these findings, SMSD/CsA-RP might be a favorable dosage form for effective and safe inhalation therapy of CsA. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure.

    PubMed

    Sigalet, David L; Brindle, Mary E; Boctor, Dana; Dicken, Bryan; Lam, Viona; Lu, Lily Sia; de Heuvel, Elaine; Hartmann, Bolette; Holst, Jens J

    2017-05-01

    Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. With parental consent (Health Canada Protocol:150,979), parenteral nutrition (PN)-dependent infants were treated with 5-20-μg/kg/day GLP-2 for 3days (phase 1), and if tolerated continued for 42days (phase 2). Nutritional therapy was by primary caregivers, and follow-up was to one year. Six patients were enrolled, age 5.4±3.2months, bowel length: 27±12% of predicted, PN dependent (67±18% of calories). GLP-2 did not affect vital signs, nor were there significant adverse events during the trial. Dosing 5μg/kg/day gave GLP-2 levels of 52-57pmol/L, with no change in half-life or endogenous GLP-2 levels. Enteral feeds, weight, Z scores, stooling frequency, and citrulline levels improved numerically. The trial was discontinued early because of a drop in potency. GLP-2 was well tolerated in infants, and pK was similar to children with no changes in endogenous GLP-2 release. The findings suggest that GLP-2 ligands may be safely used in infants and may have beneficial effects on nutritional status. Further study is required. 2b Prospective Interventional Study. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys.

    PubMed

    Boado, Ruben J; Hui, Eric K-W; Lu, Jeff Zhiqiang; Pardridge, William M

    2009-10-26

    Enzyme replacement therapy is not effective for the brain, owing to the lack of transport of the enzyme across the blood-brain barrier (BBB). Recombinant proteins such as the lysosomal enzyme, iduronidase, can penetrate the human BBB, following the re-engineering of the protein as an IgG fusion protein, where the IgG moiety targets an endogenous BBB transport system. The IgG acts as a molecular Trojan horse to ferry the fused protein into brain. AGT-181 is a genetically engineered fusion protein of human iduronidase and a chimeric monoclonal antibody against the human insulin receptor. Adult Rhesus monkeys were administered repeat intravenous doses of AGT-181 ranging from 0.2 to 20 mg/kg. Chronic AGT-181 dosing resulted in no toxicity at any dose, no changes in organ histology, no change in plasma or cerebrospinal fluid glucose, and no significant immune response. AGT-181 was rapidly removed from plasma, based on measurements of either plasma immunoreactive AGT-181 or plasma iduronidase enzyme activity. Plasma pharmacokinetics analysis showed a high systemic volume of distribution, and a clearance rate comparable to a small molecule. The safety pharmacology studies provide the basis for future drug development of AGT-181 as a new therapeutic approach to treatment of the brain in Hurler's syndrome.

  2. The Effect of Food and Formulation on the Pharmacokinetics, Safety, and Tolerability of GSK1322322 in Healthy Volunteers

    PubMed Central

    Naderer, Odin; Jones, Lori S; Zhu, John; Coffin, Mark D; Kurtinecz, Milena; Dumont, Etienne

    2015-01-01

    GSK1322322 is the first in a new class of antibiotics that inhibit peptide deformylase, necessary for bacterial protein maturation. Previously, low absolute bioavailability was observed for the 1500-mg oral tablet formulation, resulting in a less than dose-proportional increase from the 1000-mg dose. Furthermore, high variability of pharmacokinetic (PK) parameters within cohorts was suggested to be associated with differences in body weight. This open-label, randomized, 4-period, crossover, single-dose phase I study in healthy individuals compared the PK, safety, and tolerability of free base oral tablets under fasted or fed conditions with intravenous and oral mesylate salt solution of GSK1322322 under fasted conditions. Absolute bioavailability of GSK1322322 1500-mg free base tablets under fasted conditions, fed conditions, and oral mesylate salt solution was 57%, 77%, and 92%, respectively. Moderate-fat/calorie food intake increased area under the concentration–time curve (AUC0−∞) by 36%, maintained maximum observed concentration (Cmax), and delayed time to Cmax. It appeared that AUC0−∞ decreased with body weight, whereas clearance increased. GSK1322322 administration resulted in only mild-to-moderate adverse events. These results support future clinical investigations of the free base oral tablet formulation of GSK1322322 1500 mg after intake of a moderate-fat/calorie meal, including further investigation of a potential weight-based dosage change. PMID:26097792

  3. Intra-articular administration of lidocaine in anaesthetized dogs: pharmacokinetic profile and safety on cardiovascular and nervous systems.

    PubMed

    Di Salvo, A; Bufalari, A; De Monte, V; Cagnardi, P; Marenzoni, M L; Catanzaro, A; Vigorito, V; Della Rocca, G

    2015-08-01

    The intra-articular administration of lidocaine is a frequent practice in human orthopaedic surgical procedures, but an eventual absorption of the drug into the bloodstream can lead to toxicity, mainly concerning the central nervous system and the cardiovascular systems. The purpose of this study was to determine the pharmacokinetic profile and the safety, in terms of cardiovascular and CNS toxicity, of lidocaine after intra-articular administration to anesthetized dogs undergoing arthroscopy. Lidocaine 2% was administered to eight dogs before surgery in differing amounts, depending on the volume of the joints involved, and blood samples were taken at predetermined time points. The maximum serum concentration of lidocaine ranged from 0.50 to 3.01 μg/mL (mean ± SD: 2.18 ± 0.91 μg/mL), and the time to reach it was 28.75 ± 15.74 min. No signs of cardiac toxicity were detected during the entire procedure, and possible signs of CNS toxicity were masked by the anaesthesia. However, concentrations reported in literature as responsible for neurotoxicity in dog were achieved in three of eight investigated subjects. Pending further studies, veterinarians should consider the possibility of side effects occurring following the intra-articular administration of local anaesthetics.

  4. Adult and paediatric poor metabolisers of desloratadine: an assessment of pharmacokinetics and safety.

    PubMed

    Prenner, Bruce; Kim, Kenneth; Gupta, Samir; Khalilieh, Sauzanne; Kantesaria, Bhavna; Manitpisitkul, Prasarn; Lorber, Richard; Wang, Zaiqi; Lutsky, Barry

    2006-03-01

    Antihistamines are widely used to treat allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) in adults and children. Desloratadine is a once-daily oral antihistamine with a favourable sedation profile that is approved for the treatment of AR and CIU. Phenotypic polymorphism in the metabolism of desloratadine has been observed, such that some individuals have a decreased ability to form 3-hydroxydesloratadine, the major metabolite of desloratadine; such individuals are termed 'poor metabolisers of desloratadine'. This review describes the prevalence of poor metabolisers of desloratadine, quantifies the exposure to desloratadine in poor metabolisers and demonstrates that the increased exposure in poor metabolisers is independent of age when administered at age-appropriate doses. Furthermore, this review demonstrates that the increased exposure to desloratadine in poor metabolisers is not associated with any changes in the safety and tolerability profile of desloratadine, including cardiovascular safety.

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

    SciTech Connect

    Trifilieff, Alexandre; Ethell, Brian T.; Sykes, David A.; Watson, Kenny J.; Collingwood, Steve; Charlton, Steven J.; Kent, Toby C.

    2015-08-15

    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 1 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 lower M

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

    PubMed

    Trifilieff, Alexandre; Ethell, Brian T; Sykes, David A; Watson, Kenny J; Collingwood, Steve; Charlton, Steven J; Kent, Toby C

    2015-08-15

    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 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 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 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium.

  7. Evaluation of residue drum storage safety risks

    SciTech Connect

    Conner, W.V.

    1994-06-17

    A study was conducted to determine if any potential safety problems exist in the residue drum backlog at the Rocky Flats Plant. Plutonium residues stored in 55-gallon drums were packaged for short-term storage until the residues could be processed for plutonium recovery. These residues have now been determined by the Department of Energy to be waste materials, and the residues will remain in storage until plans for disposal of the material can be developed. The packaging configurations which were safe for short-term storage may not be safe for long-term storage. Interviews with Rocky Flats personnel involved with packaging the residues reveal that more than one packaging configuration was used for some of the residues. A tabulation of packaging configurations was developed based on the information obtained from the interviews. A number of potential safety problems were identified during this study, including hydrogen generation from some residues and residue packaging materials, contamination containment loss, metal residue packaging container corrosion, and pyrophoric plutonium compound formation. Risk factors were developed for evaluating the risk potential of the various residue categories, and the residues in storage at Rocky Flats were ranked by risk potential. Preliminary drum head space gas sampling studies have demonstrated the potential for formation of flammable hydrogen-oxygen mixtures in some residue drums.

  8. 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.

  9. Formulation and Pharmacokinetic Evaluation of Microcapsules Containing Pravastatin Sodium Using Rats

    PubMed Central

    Karki, Roopa; Goli, Divakar; Mudagal, Manjunatha Panduranga

    2016-01-01

    Pravastatin Sodium has a cholesterol lowering agent. It has shorter half-life and undergoes first-pass metabolism. Frequent dose is required in case of conventional dosage form. The purpose of the study is to formulate and evaluate microcapsules containing Pravastatin Sodium by complex with cholestyramine resins coated with Eudragit RLPO and Eudragit RSPO polymers for achieving control release. Complexation of drug on resin was carried out by batch method. Microencapsulation was carried out by nonaqueous solvent evaporation method. Pharmacokinetic studies were done by using rats. The intermediate stability studies were carried out on the most satisfactory formulations. FTIR, X-ray diffraction, and DSC spectra of drug, drug-resinates, and polymers revealed no chemical interaction. The % DEE and % yield were observed for formulations of f1 to f7 that were varied from 97.1 ± 0.8 to 98.9 ± 0.5% and 95.0 ± 3.25 to 98.8 ± 7.1%, respectively. Most satisfactory formulation, f6, showed drug release up to 72.6%. No changes in % DEE and % CDR were observed after stability studies. Microcapsules of f6 formulation achieved best performance regarding in vitro drug release and from pharmacokinetic evaluation mean residence time was found to be 6.3 h, thus indicated, Pravastatin Sodium microcapsules were released and absorbed slowly over a prolonged period of time. PMID:27595040

  10. Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against ebola virus and marburg virus: results of two single-ascending-dose studies.

    PubMed

    Heald, Alison E; Iversen, Patrick L; Saoud, Jay B; Sazani, Peter; Charleston, Jay S; Axtelle, Tim; Wong, Michael; Smith, William B; Vutikullird, Apinya; Kaye, Edward

    2014-11-01

    Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.

  11. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease.

    PubMed

    Maertens, Johan; Cornely, Oliver A; Ullmann, Andrew J; Heinz, Werner J; Krishna, Gopal; Patino, Hernando; Caceres, Maria; Kartsonis, Nicholas; Waskin, Hetty; Robertson, Michael N

    2014-07-01

    This was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (n = 10) were compared with those of a placebo (n = 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (n = 21) and 300 mg q.d. (n = 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {Cavgs}], of ≥ 500 to ≤ 2,500 ng/ml in ≥ 90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-state Cavg, ∼ 1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01075984.).

  12. Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-Experienced HIV-1 Infected Adolescents: 48-Week Results from IMPAACT P1093

    PubMed Central

    Viani, Rolando M.; Alvero, Carmelita; Fenton, Terry; Acosta, Edward P.; Hazra, Rohan; Townley, Ellen; Steimers, Debra; Min, Sherene; Wiznia, Andrew

    2015-01-01

    Objective To assess the pharmacokinetic (PK), safety and efficacy of dolutegravir plus optimized background regimen (OBR) in HIV infected treatment-experienced adolescents. Methods Children ≥12 to < 18 years received dolutegravir weight-based fixed doses at ~1.0 mg/kg once daily in a Phase I/II multicenter open-label 48 week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through Week 48. Results Twenty three adolescents, were enrolled and 22 (96%) completed the 48 week study visit. Median age and weight were 15 years and 52 kg, respectively. Median (IQR) baseline CD4+ cell count was 466 cells/µL (297, 771). Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 copies/mL (3.9, 4.6). Dolutegravir geometric mean AUC(0–24) and C24 were 46.0 µg.h/mL and 0.90 µg/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA < 400 copies/mL was achieved in 74 % (95% CI: 52% to 90%) at Week 48. Additionally, 61% (95% CI: 39% to 80%) had an HIV RNA < 50 copies/mL at Week 48. Median (IQR) gain in CD4 cell count at Week 48 was 84 cells/µL (−81, 238). Dolutegravir was well tolerated, with no Grade 4 AEs, SAEs or discontinuations due to AEs. Conclusions Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through Week 48. PMID:26244832

  13. 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

    2017-09-07

    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 AUCtau,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 Cmax,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.

  14. Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD.

    PubMed

    Moorthy, Ganesh; Sallee, Floyd; Gabbita, Prasad; Zemlan, Frank; Sallans, Larry; Desai, Pankaj B

    2015-10-01

    Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.

  15. Exploring flubendazole formulations for use in sheep. Pharmacokinetic evaluation of a cyclodextrin-based solution

    PubMed Central

    2012-01-01

    Background Flubendazole (FLBZ) is a poor water solubility broad-spectrum BZD methylcarbamate anthelmintic compound. Cyclodextrins (CDs) are usually used to increase aqueous solubility of poor hydrosoluble compounds. The comparative in vitro aqueous solubility of FLBZ and other BZD anthelmintics in the presence of hydroxypropyl-β-cyclodextrin (HPβCD) was evaluated in the current work. Additionally, the comparative pharmacokinetic behaviour of FLBZ (and its metabolites) administered by the intraruminal (i.r.) or intraabomasal (i.a.) routes to sheep as either an aqueous CDs-based solution or a conventional carboximethylcellulose (CMC) suspension was assessed. Drug solubility studies involving albendazole, mebendazole, oxfendazole and FLBZ were performed in an aqueous solution (pH 1.2 or 7.4) with or without HPβCD (10%, w/v). The pharmacokinetic study involved two experiments. Experiment 1: In a crossover study, sheep received either a FLBZ-CDs solution (n = 3) or a FLBZ-CMC suspension (n = 3) by the i.r. route (3.8 mg/kg). The treatment Groups were reversed after a 21-days washout period. Experiment 2: sheep (n = 4) were treated by the i.a. route with the FLBZ-CDs solution (3.8 mg/kg). Plasma and abomasal fluid samples were collected between 0 and 72 h post-treatment. Samples were analysed by HPLC. Results Improvement of FLBZ aqueous solubility due to CDs resulted markedly higher than that observed for mebendazole and albendazole. However, oppositely to what was expected, the absorption-related pharmacokinetic parameters did not show any marked formulation-dependant effect. After the i.a. administration of FLBZ, the AUC and the Tmax of the parent compound were significantly (P < 0.05) reduced, which is consistent with ruminal bypass. Conclusion The administration of FLBZ as a CDs-based solution, does not seem to achieve great practical relevance for parasite control in sheep. PMID:22640491

  16. Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor.

    PubMed

    Denti, Paolo; Sharp, Sarah-Kate; Kröger, Wendy L; Schwager, Sylva L; Mahajan, Aman; Njoroge, Mathew; Gibhard, Liezl; Smit, Ian; Chibale, Kelly; Wiesner, Lubbe; Sturrock, Edward D; Davies, Neil H

    2014-06-02

    Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5 nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC-MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1 mg/kg bodyweight intravenously, 5 mg/kg bodyweight orally. The Cmax obtained following oral administration of the drug was 0.082 μM and LisW-S had an apparent terminal elimination half-life of around 3.1 h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Systematic safety evaluation on photoluminescent carbon dots

    NASA Astrophysics Data System (ADS)

    Wang, Kan; Gao, Zhongcai; Gao, Guo; Wo, Yan; Wang, Yuxia; Shen, Guangxia; Cui, Daxiang

    2013-03-01

    Photoluminescent carbon dots (C-dots) were prepared using the improved nitric acid oxidation method. The C-dots were characterized by tapping-mode atomic force microscopy, and UV-vis absorption spectroscopy. The C-dots were subjected to systematic safety evaluation via acute toxicity, subacute toxicity, and genotoxicity experiments (including mouse bone marrow micronuclear test and Salmonella typhimurium mutagenicity test). The results showed that the C-dots were successfully prepared with good stability, high dispersibility, and water solubility. At all studied C-dot dosages, no significant toxic effect, i.e., no abnormality or lesion, was observed in the organs of the animals. Therefore, the C-dots are non-toxic to mice under any dose and have potential use in fluorescence imaging in vivo, tumor cell tracking, and others.

  18. Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected with Aspergillus Species and Other Filamentous Fungi: Maximum Tolerated Dose Study

    PubMed Central

    Walsh, Thomas J.; Goodman, Jesse L.; Pappas, Peter; Bekersky, Ihor; Buell, Donald N.; Roden, Maureen; Barrett, John; Anaissie, Elias J.

    2001-01-01

    We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (Cmax) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 μg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC24) changed to 692, 1,062, 860, and 554 μg · h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of ≥7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These

  19. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study.

    PubMed

    Walsh, T J; Goodman, J L; Pappas, P; Bekersky, I; Buell, D N; Roden, M; Barrett, J; Anaissie, E J

    2001-12-01

    We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C(max)) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 microg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC(24)) changed to 692, 1,062, 860, and 554 microg x h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >or=7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n

  20. Note on evaluating safety performance of road infrastructure to motivate safety competition.

    PubMed

    Han, Sangjin

    2016-01-01

    Road infrastructures are usually developed and maintained by governments or public sectors. There is no competitor in the market of their jurisdiction. This monopolic feature discourages road authorities from improving the level of safety with proactive motivation. This study suggests how to apply a principle of competition for roads, in particular by means of performance evaluation. It first discusses why road infrastructure has been slow in safety oriented development and management in respect of its business model. Then it suggests some practical ways of how to promote road safety between road authorities, particularly by evaluating safety performance of road infrastructure. These are summarized as decision of safety performance indicators, classification of spatial boundaries, data collection, evaluation, and reporting. Some consideration points are also discussed to make safety performance evaluation on road infrastructure lead to better road safety management.

  1. [Review of pharmacokinetic monitoring of 5-Fluorouracil as a tool to increase efficacy and safety].

    PubMed

    Matus-Santos, Juan Antonio; Aguilar-Ponce, José Luis; Lara-Medina, Fernando Ulises; Herrera-Gómez, Ángel; Meneses-García, Abelardo; López-Gamboa, Mireya

    2016-01-01

    Recent progress in medical knowledge has indicated that both clinical and biological markers will determine the response to different medical treatments: age, gender and genetics will determine the success of treatment. Genetic variability in this respect is fundamental and determines efficiency and safety of drugs, as well as susceptibility and illness' development. Fortunately, personalized medicine now offers individually tailored treatment strategies for each patient's needs. This is of outmost importance in oncology, since treatment is per se toxic and the commonly found low serum drug concentrations result in low treatment efficacy. Personalized medicine will allow a better approach to this, until now, a poorly managed disease. In this review we intent to raise awareness of personalized medicine and of clinical pharmacologic monitoring, with the aim to achieve adequate levels of efficacy and safety in the use of the cytotoxic drug 5-Fluorouracil (5-FU). Additionally, the importance of pharmacogenomics for the use of 5-FU is discussed. We designed this discussion towards medical practitioners challenged with treatment decisions every day, together with their patients.

  2. Evaluation of the Population Pharmacokinetic Properties of Lidocaine and its Metabolites After Long-Term Multiple Applications of a Lidocaine Plaster in Post-Herpetic Neuralgia Patients.

    PubMed

    Bursi, Roberta; Piana, Chiara; Grevel, Joachim; Huntjens, Dymphy; Boesl, Irmgard

    2017-01-12

    Lidocaine 5% medicated plaster is the first lidocaine containing product for chronic use. As no previous investigations have been conducted to evaluate the population pharmacokinetics of long-term exposure to lidocaine 5% medicated plasters, further insights into the evaluation of the pharmacokinetic properties of lidocaine and its metabolites were needed for the assessment of its safety. The population pharmacokinetic properties of lidocaine and its metabolites were evaluated after multiple applications of lidocaine 5% medicated plasters based on data collected for up to 14.5 months from two phase III clinical trials (up to 2.5 months in the first trial, and up to 12 months in a follow-up trial) in post-herpetic neuralgia patients. Modeling was performed using nonlinear mixed effects as implemented in NONMEM(®) (nonlinear mixed-effect modeling) v.5. A stepwise forward inclusion and backward elimination procedure were used for covariate model building. The model provides reliable estimates of the pharmacokinetic behavior of lidocaine after medicated plaster application. It was validated using simulations and showed adequate predictive properties. Apparent Clearance was estimated to be 48 L/h after application of two or fewer plasters, whereas its value increased to 67 L/h after application of three plasters. Model-based simulations predicted no accumulation of lidocaine or any of its metabolites after long-term exposure of three simultaneous plasters up to 1 year. The variability explained by adding covariates into the model for the long-term exposures of lidocaine following one plaster or three simultaneous plaster applications was found to be very small with respect to the overall between-subject variability. In conclusion, exposure to lidocaine after the application of the lidocaine medicated plaster was found to be primarily affected by the number of plasters simultaneously applied, i.e., it increased with the number of applied patches, but less than

  3. A Phase 1 Study of 131I-CLR1404 in Patients with Relapsed or Refractory Advanced Solid Tumors: Dosimetry, Biodistribution, Pharmacokinetics, and Safety

    PubMed Central

    Grudzinski, Joseph J.; Titz, Benjamin; Kozak, Kevin; Clarke, William; Allen, Ernest; Trembath, LisaAnn; Stabin, Michael; Marshall, John; Cho, Steve Y.; Wong, Terence Z.; Mortimer, Joanne; Weichert, Jamey P.

    2014-01-01

    Introduction 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404. Methods Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15–35 minutes, 4–6, 18–24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software. Results Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng•hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow. Conclusions Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. Trial Registration ClinicalTrials.gov NCT00925275 PMID:25402488

  4. In silico evaluation of gadofosveset pharmacokinetics in different population groups using the Simcyp® simulator platform.

    PubMed

    Spanakis, Marios; Marias, Kostas

    2014-12-01

    Gadofosveset is a Gd-based contrast agent used for magnetic resonance imaging (MRI). Gadolinium kinetic distribution models are implemented in T1-weighted dynamic contrast-enhanced perfusion MRI for characterization of lesion sites in the body. Physiology changes in a disease state potentially can influence the pharmacokinetics of drugs and to this respect modify the distribution properties of contrast agents. This work focuses on the in silico modelling of pharmacokinetic properties of gadofosveset in different population groups through the application of physiologically-based pharmacokinetic models (PBPK) embedded in Simcyp® population pharmacokinetics platform. Physicochemical and pharmacokinetic properties of gadofosveset were introduced into Simcyp® simulator platform and a min-PBPK model was applied. In silico clinical trials were generated simulating the administration of the recommended dose for the contrast agent (i.v., 30 mg/kg) in population cohorts of healthy volunteers, obese, renal and liver impairment, and in a generated virtual oncology population. Results were evaluated regarding basic pharmacokinetic parameters of Cmax, AUC and systemic CL and differences were assessed through ANOVA and estimation of ratio of geometric mean between healthy volunteers and the other population groups. Simcyp® predicted a mean Cmax = 551.60 mg/l, a mean AUC = 4079.12 mg/L*h and a mean systemic CL = 0.56 L/h for the virtual population of healthy volunteers. Obese population showed a modulation in Cmax and CL, attributed to increased administered dose. In renal and liver impairment cohorts a significant modulation in Cmax, AUC and CL of gadofosveset is predicted. Oncology population exhibited statistical significant differences regarding AUC when compared with healthy volunteers. This work employed Simcyp® population pharmacokinetics platform in order to compute gadofosveset's pharmacokinetic profiles through PBPK models and in silico clinical

  5. 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

  6. Single, Escalating Dose Pharmacokinetics, Safety and Food Effects of a New Oral Androgen Dimethandrolone Undecanoate in Man: A prototype oral male hormonal contraceptive

    PubMed Central

    Swerdloff, Ronald S.; Nya-Ngatchou, Jean Jacques; Liu, Peter Y.; Amory, John K.; Leung, Andrew; Hull, Laura; Blithe, Diana L.; Woo, Jason; Bremner, William J.; Wang, Christina

    2014-01-01

    The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer-acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25 to 800 mg), ten male volunteers received DMAU and two received placebo at two academic medical centers. DMAU was administered both fasting and after a high fat meal (200–800 mg doses). Serial serum samples were collected over 24h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200mg DMAU and showed a dose-incremental increase up to 800mg, with peak levels 4 to 8h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12h after DMAU administration with food at doses above 200mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics. PMID:24789057

  7. Criticality Safety Evaluation of a LLNL Training Assembly for Criticality Safety (TACS)

    SciTech Connect

    Heinrichs, D P

    2006-06-26

    Hands-on experimental training in the physical behavior of multiplying systems is one of ten key areas of training required for practitioners to become qualified in the discipline of criticality safety as identified in DOE-STD-1135-99, ''Guidance for Nuclear Criticality Safety Engineer Training and Qualification''. This document is a criticality safety evaluation of the training activities (or operations) associated with HS-3200, ''Laboratory Class for Criticality Safety''. These activities utilize the Training Assembly for Criticality Safety (TACS). The original intent of HS-3200 was to provide LLNL fissile material handlers with a practical hands-on experience as a supplement to the academic training they receive biennially in HS-3100, ''Fundamentals of Criticality Safety'', as required by ANSI/ANS-8.20-1991, ''Nuclear Criticality Safety Training''. HS-3200 is to be enhanced to also address the training needs of nuclear criticality safety professionals under the auspices of the NNSA Nuclear Criticality Safety Program.

  8. A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis.

    PubMed

    Saluja, Sonal; Kasha, Purna C; Paturi, Jyotsna; Anderson, Carter; Morris, Russell; Banga, Ajay K

    2013-09-10

    The nature of Alzheimer's disease limits the effectiveness of available oral treatments. The aim of this study was to assess the feasibility of transdermal iontophoretic delivery of donepezil in a hairless rat model as a potential treatment modality in Alzheimer's and to evaluate the effect of current densities on its pharmacokinetics. Donepezil loaded integrated Wearable Electronic Drug Delivery (WEDD(®)) patches supplied current levels of 0, 0.13, 0.26 and 0.39 mA. Plasma extracted donepezil was analyzed by HPLC. Noncompartmental analysis was used to characterize disposition of the drug. The amount delivered across hairless rat skin and areas under the curve (AUC) were found to rise in proportion to the current levels. Peak plasma levels of 0.094, 0.237 and 0.336 μg/ml were achieved at 0.13, 0.26 and 0.39 mA respectively. Time to peak plasma concentrations was after termination of current and same for all current levels. Transdermal elimination half-life was significantly increased from the true value of 3.2h due to depot formation, prolonging complete absorption of the drug. Donepezil was successfully delivered iontophoretically at levels sufficient to produce pharmacodymanic effect. Pharmacokinetic analysis demonstrated linear kinetics at the current levels used and flip flop kinetics following iontophoretic administration. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. A validated bioanalytical HPLC method for pharmacokinetic evaluation of 2-deoxyglucose in human plasma.

    PubMed

    Gounder, Murugesan K; Lin, Hongxia; Stein, Mark; Goodin, Susan; Bertino, Joseph R; Kong, Ah-Ng Tony; DiPaola, Robert S

    2012-05-01

    2-Deoxyglucose (2-DG), an analog of glucose, is widely used to interfere with glycolysis in tumor cells and studied as a therapeutic approach in clinical trials. To evaluate the pharmacokinetics of 2-DG, we describe the development and validation of a sensitive HPLC fluorescent method for the quantitation of 2-DG in plasma. Plasma samples were deproteinized with methanol and the supernatant was dried at 45°C. The residues were dissolved in methanolic sodium acetate-boric acid solution. 2-DG and other monosaccharides were derivatized to 2-aminobenzoic acid derivatives in a single step in the presence of sodium cyanoborohydride at 80°C for 45 min. The analytes were separated on a YMC ODS C₁₈ reversed-phase column using gradient elution. The excitation and emission wavelengths were set at 360 and 425 nm. The 2-DG calibration curves were linear over the range of 0.63-300 µg/mL with a limit of detection of 0.5 µg/mL. The assay provided satisfactory intra-day and inter-day precision with RSD less than 9.8%, and the accuracy ranged from 86.8 to 110.0%. The HPLC method is reproducible and suitable for the quantitation of 2-DG in plasma. The method was successfully applied to characterize the pharmacokinetics profile of 2-DG in patients with advanced solid tumors.

  10. Efficacy, safety and pharmacokinetics of indacaterol in Caucasian and Japanese patients with chronic obstructive pulmonary disease: a comparison of data from two randomized, placebo-controlled studies.

    PubMed

    Hosoe, Motoi; Woessner, Ralph; Matsushima, Soichiro; Lawrence, David; Kramer, Benjamin

    2011-01-01

    Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β2-adrenoceptor agonist that has been approved in the EU for the treatment of chronic obstructive pulmonary disease (COPD). Ethnic differences may influence the pharmacokinetics and pharmacodynamics of a drug, and it is therefore important to compare these parameters in different populations. To compare the efficacy, safety and pharmacokinetics of indacaterol between Caucasian and Japanese patients with COPD. Data from two randomized, double-blind, single-dose crossover, placebo-controlled studies in Caucasian and Japanese patients with moderate-to-severe COPD were compared. The two studies were similar in terms of study design, study population (inclusion/exclusion criteria), parameters examined and the indacaterol doses (150, 300 or 600 μg) tested. Efficacy (primary endpoint: 24-hour post-dose [trough] forced expiratory volume in 1 second [FEV1]), pharmacokinetics, and safety were assessed for 24 hours post-dose in each treatment period. Fifty-one Caucasian (86.3% male; mean age 61.8 years) patients were randomized into the first study and 50 Japanese (92.0% male; mean age 67.2 years) patients were randomized into the second study; ≥90% of patients completed the studies. In both studies, 24-hour post-dose trough FEV1 was significantly higher for all indacaterol doses versus placebo (p<0.001), with clinically relevant differences of 140 and 130 mL for the lowest (150 μg) dose in the Caucasian and Japanese studies, respectively. In both studies, single doses of indacaterol provided improvements in FEV1 that were sustained for 24 hours (p<0.001 vs placebo at all time points). In both populations, the average maximum serum concentration (Cmax) of indacaterol was observed at the first sampling time point and pharmacokinetic profiles were similar between populations. The increase in exposure (Cmax and area under the serum concentration-time curve from time zero to 24 hours) with increasing

  11. Comparison of the pharmacokinetics, safety, and immunogenicity of MSB11022, a biosimilar of adalimumab, with Humira(®) in healthy subjects.

    PubMed

    Hyland, Elizabeth; Mant, Tim; Vlachos, Pantelis; Attkins, Neil; Ullmann, Martin; Roy, Sanjeev; Wagner, Volker

    2016-10-01

    The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of the proposed adalimumab biosimilar MSB11022 (Merck) with Humira(®) (AbbVie), sourced from both the US (US reference product [US-RP]) and Europe (European reference medicinal product [EU-RMP]). In this phase 1 double-blind, parallel group trial (EMR200588-001), 213 healthy volunteers were randomized 1 : 1 : 1 to receive a single dose (40 mg) of MSB11022, US-RP or EU-RMP in order to achieve 80% power assuming a 5% difference among groups and a 10% dropout rate. Following a preplanned blinded sample size re-assessment after more than 50% of the originally planned subjects had been observed, the sample size was increased to 237 (79 per arm) to ensure 213 completers. Primary PK endpoints analyzed by non-compartmental methods, were area under the curve (AUC) from time 0 extrapolated to infinity (AUC(0,∞)), maximum observed concentration (Cmax ), and AUC from time 0 to the last quantifiable concentration (AUC(0,tlast )). PK equivalence was declared if the 90% CI for the test : reference ratio lay within the 80-125% equivalence margin. Bioequivalence was demonstrated if all three PK parameters met the PK equivalence criteria. Safety and tolerability were also evaluated. Mean serum concentration-time profiles for the three treatments were similar. MSB11022 demonstrated PK equivalence to US-RP and EU-RMP for all primary endpoints. The geometric means of AUC(0,∞), Cmax and AUC(0,tlast ) following a single dose of MSB11022 were 2276.05 μg ml(-1)  h, 3.44 μg ml(-1)   and 1983.90 μg ml(-1)  h, respectively. Adverse events (AEs) were similar across all groups, with treatment-emergent AEs (TEAEs) reported by 62.8%, 56.3% and 62.0% of subjects within the MSB11022, US-RP and EU-RMP groups, respectively. Most of the TEAEs were considered mild and unrelated to study drug. No deaths or severe AEs related to the study drug were reported. Bioequivalence between MSB11022, US

  12. Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus Type-1-Infected Children 4 Weeks to 2 Years of Age

    PubMed Central

    Nachman, Sharon; Alvero, Carmelita; Acosta, Edward P.; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Rizk, Matthew L.; Spector, Stephen A.; Frenkel, Lisa M.; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew

    2015-01-01

    Background IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth. Methods Dose selection of the oral suspension formulation for each cohort (IV: 6 months to <2 years and V: 4 weeks to <6 months) was based on review of short-term safety (4 weeks) and intensive PK evaluation. Safety data through Weeks 24 and 48 and Grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction from baseline at Week 24 (Success). For Cohort IV, optimized background therapy (OBT) could have been initiated with RAL either at study entry or after intensive PK sampling was completed at Day 5–12. An OBT was started when RAL was initiated for Cohort V subjects because they were not permitted to have received direct antiretroviral therapy before enrollment. Results Total accrual was 27 subjects in these 2 cohorts, including 1 subject who was enrolled but never started study drug (excluded from the analyses). The targeted PK parameters (area under the curve [AUC]0−12hr and C12hr) were achieved for each cohort allowing for dose selection. Through Week 48, there were 10 subjects with Grade 3+ AEs. Two were judged related to study drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune reconstitution syndrome, and no drug-related deaths. At Week 48, for Cohorts IV and V, 87.5% of subjects achieved virologic success and 45.5% had HIV RNA <50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm3 and 7.3% were observed. Conclusions A total of 6 mg/kg per dose twice daily of RAL for oral suspension was well tolerated and showed favorable virologic and immunologic responses. PMID:26582887

  13. Comparison of the pharmacokinetics, safety, and immunogenicity of MSB11022, a biosimilar of adalimumab, with Humira® in healthy subjects

    PubMed Central

    Mant, Tim; Vlachos, Pantelis; Attkins, Neil; Ullmann, Martin; Roy, Sanjeev; Wagner, Volker

    2016-01-01

    Aims The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of the proposed adalimumab biosimilar MSB11022 (Merck) with Humira® (AbbVie), sourced from both the US (US reference product [US‐RP]) and Europe (European reference medicinal product [EU‐RMP]). Methods In this phase 1 double‐blind, parallel group trial (EMR200588‐001), 213 healthy volunteers were randomized 1 : 1 : 1 to receive a single dose (40 mg) of MSB11022, US‐RP or EU‐RMP in order to achieve 80% power assuming a 5% difference among groups and a 10% dropout rate. Following a preplanned blinded sample size re‐assessment after more than 50% of the originally planned subjects had been observed, the sample size was increased to 237 (79 per arm) to ensure 213 completers. Primary PK endpoints analyzed by non‐compartmental methods, were area under the curve (AUC) from time 0 extrapolated to infinity (AUC(0,∞)), maximum observed concentration (C max), and AUC from time 0 to the last quantifiable concentration (AUC(0,t last)). PK equivalence was declared if the 90% CI for the test : reference ratio lay within the 80–125% equivalence margin. Bioequivalence was demonstrated if all three PK parameters met the PK equivalence criteria. Safety and tolerability were also evaluated. Results Mean serum concentration–time profiles for the three treatments were similar. MSB11022 demonstrated PK equivalence to US‐RP and EU‐RMP for all primary endpoints. The geometric means of AUC(0,∞), C max and AUC(0,t last) following a single dose of MSB11022 were 2276.05 μg ml–1 h, 3.44 μg ml–1  and 1983.90 μg ml–1 h, respectively. Adverse events (AEs) were similar across all groups, with treatment‐emergent AEs (TEAEs) reported by 62.8%, 56.3% and 62.0% of subjects within the MSB11022, US‐RP and EU‐RMP groups, respectively. Most of the TEAEs were considered mild and unrelated to study drug. No deaths or severe AEs related to the study drug were

  14. 21 CFR 601.35 - Evaluation of safety.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... diagnostic radiopharmaceutical by radiation dosimetry evaluations in humans and appropriate animal models... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Evaluation of safety. 601.35 Section 601.35 Food... LICENSING Diagnostic Radiopharmaceuticals § 601.35 Evaluation of safety. (a) Factors considered in...

  15. 21 CFR 315.6 - Evaluation of safety.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... diagnostic radiopharmaceutical by radiation dosimetry evaluations in humans and appropriate animal models... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Evaluation of safety. 315.6 Section 315.6 Food and... USE DIAGNOSTIC RADIOPHARMACEUTICALS § 315.6 Evaluation of safety. (a) Factors considered in the...

  16. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    PubMed Central

    2006-01-01

    Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients. Results In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = -33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .5015, 95% 1-sided CI = -33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 681750 ng/mL). Conclusion Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study.

  17. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    PubMed Central

    Montaner, Julio S.G.; Schutz, Malte; Schwartz, Robert; Jayaweera, Dushyantha T.; Burnside, Alfred F.; Walmsley, Sharon; Saag, Michael S.

    2006-01-01

    Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients. Results In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = −33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .5015, 95% 1-sided CI = −33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 68-1750 ng/mL). Conclusions Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study. PMID:16926775

  18. Impact on abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin.

    PubMed

    Bernard, Apexa; Vaccaro, Nicole; Acharya, Milin; Jiao, James; Monbaliu, Johan; De Vries, Ronald; Stieltjes, Hans; Yu, Margaret; Tran, Namphuong; Chien, Caly

    2015-01-01

    We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11-16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8-13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax ) and 15% for area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration (AUClast ) and AUC from time 0 to infinity (AUC∞ ) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.

  19. Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell®)

    PubMed Central

    Dautzenberg, Bertrand; Nides, Mitchell; Kienzler, Jean-Luc; Callens, Anne

    2007-01-01

    Background The use of nicotine replacement therapy (NRT) can almost double the chances of success for smokers to quit. Nevertheless, there is still a considerable number of cessation attempts that are made without any treatment. This novel oral formulation, (lozenge containing nicotine bitartrate dihydrate) has been developed to enlarge the offer for efficient smoking cessation drug therapies, assuming that increasing treatment options will bring more smokers to find the support they personally need to stop smoking. Methods Three pharmacokinetic (PK), one safety and two efficacy studies were carried out with Nicotinell lozenges. PK trials were: (1) a single-dose, three-way crossover study comparing 1 and 2 mg lozenges with 2 mg nicotine gum; (2) a multiple-dose, two-way crossover study comparing 1 mg lozenge with 2 mg gum; (3) a multiple-dose, three-way crossover study comparing 1 and 2 mg lozenges with 4 mg gum. Safety trial: (4) a single dose study to assess the safety of swallowing up to 12 lozenges containing 1 mg nicotine. Efficacy trials: two efficacy studies in (5) France and (6) the USA, including more than 900 smokers followed-up for up to one year, conducted with the 1 mg lozenge. Results The results of the individual PK trials showed that the 1 mg Nicotinell lozenge is bioequivalent to 2 mg polacrilex gum, as demonstrated by similar blood PK parameters (tmax, Cmax, AUC). The 2 mg lozenge was found to deliver quantities of nicotine that were intermediate between those delivered by 2 and 4 mg polacrilex gum. The short-term efficacy of the 1 mg lozenge in comparison with placebo was also demonstrated with significantly more subjects continuously abstinent from smoking with active lozenges on week 6 in two different populations: moderate to heavy smokers (FTND between 4 and 7) OR = 1.72 [95% CI: 1.05–2.80]; heavy to very heavy smokers (FTND 6 and over) OR = 2.87 [95% CI: 1.18–6.97]. Nicotinell lozenges were found to be safe with mainly mild and

  20. Single-dose pharmacokinetics and safety of azilsartan medoxomil in children and adolescents with hypertension as compared to healthy adults.

    PubMed

    Webb, Nicholas J A; Wells, Thomas; Tsai, Max; Zhao, Zhen; Juhasz, Attila; Dudkowski, Caroline

    2016-04-01

    This open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12-16 years [cohort 1a; n = 9]; 6-11 years [cohort 2; n = 8]; 4-5 years [cohort 3; n = 3]). Model-based simulations were performed to guide dosing, especially in 1-5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20-60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg. Exposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized C max and AUC0-∞, was ∼15-30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8-25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25-50-kg subjects require half the adult dose (10-40 mg), whereas 50-100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine). This dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).

  1. A Safety Index and Method for Flightdeck Evaluation

    NASA Technical Reports Server (NTRS)

    Latorella, Kara A.

    2000-01-01

    If our goal is to improve safety through machine, interface, and training design, then we must define a metric of flightdeck safety that is usable in the design process. Current measures associated with our notions of "good" pilot performance and ultimate safety of flightdeck performance fail to provide an adequate index of safe flightdeck performance for design evaluation purposes. The goal of this research effort is to devise a safety index and method that allows us to evaluate flightdeck performance holistically and in a naturalistic experiment. This paper uses Reason's model of accident causation (1990) as a basis for measuring safety, and proposes a relational database system and method for 1) defining a safety index of flightdeck performance, and 2) evaluating the "safety" afforded by flightdeck performance for the purpose of design iteration. Methodological considerations, limitations, and benefits are discussed as well as extensions to this work.

  2. Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug

    PubMed Central

    Shafiq, N.; Rajagopalan, S.; Kushwaha, H. N.; Mittal, N.; Chandurkar, N.; Bhalla, A.; Kaur, S.; Pandhi, P.; Puri, G. D.; Achuthan, S.; Pareek, A.; Singh, S. K.; Srivastava, J. S.; Gaur, S. P. S.; Malhotra, S.

    2014-01-01

    Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T1/2, MRT, and AUC0−∞ of the active metabolite 97/63 were 11.85 ± 1.94 h, 13.77 ± 2.05 h, and 878.74 ± 133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials. PMID:24800100

  3. Evaluating the safety and dosing of drugs in patients with liver cirrhosis by literature review and expert opinion

    PubMed Central

    Weersink, Rianne A; Bouma, Margriet; Burger, David M; Drenth, Joost P H; Hunfeld, Nicole G M; Kranenborg, Minke; Monster-Simons, Margje H; van Putten, Sandra A W; Metselaar, Herold J; Taxis, Katja; Borgsteede, Sander D

    2016-01-01

    Introduction Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis. Methods and analysis For each drug, a six-step evaluation process will be followed. (1) Available evidence on the pharmacokinetics and safety of a drug in patients with liver cirrhosis will be collected from the Summary of Product Characteristics (SmPC) and a systematic literature review will be performed. (2) Data regarding two outcomes, namely pharmacokinetics and safety, will be extracted and presented in a standardised assessment report. (3) A safety classification and dosage suggestion will be proposed for each drug. (4) An expert panel will discuss the validity and clinical relevance of this suggested advice. (5) Advices will be implemented in all relevant Clinical Decision Support Systems in the Netherlands and published on a website for patients and healthcare professionals. (6) The continuity of the advices will be guaranteed by a yearly check of new literature and comments on the advices. This protocol will be applied in the evaluation of a selection of drugs: (A) drugs used to treat (complications of) liver cirrhosis, and (B) drugs frequently prescribed to the general population. Ethics and dissemination Since this study does not directly involve human participants, it does not require ethical clearance. Besides implementation on a website and in clinical decision support systems, we aim to publish the generated advices of one or two drug classes in a peer-reviewed journal and at conference meetings. PMID:27733414

  4. Population pharmacokinetics. A regulatory perspective.

    PubMed

    Sun, H; Fadiran, E O; Jones, C D; Lesko, L; Huang, S M; Higgins, K; Hu, C; Machado, S; Maldonado, S; Williams, R; Hossain, M; Ette, E I

    1999-07-01

    The application of population approaches to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents. Population pharmacokinetic (and pharmacodynamic) techniques enable identification of the sources of inter- and intra-individual variability that impinge upon drug safety and efficacy. This article briefly discusses the 2-stage approach to the estimation of population pharmacokinetic parameters, which requires serial multiple measurements on each participant, and comprehensively reviews the nonlinear mixed-effects modelling approach, which can be applied in situations where extensive sampling is not done on all or any of the participants. Certain preliminary information, such as the compartment model used in describing the pharmacokinetics of the drug, is required for a population pharmacokinetic study. The practical design considerations of the location of sampling times, number of samples/participants and the need to sample an individual more than once should be borne in mind. Simulation may be useful for choosing the study design that will best meet study objectives. The objectives of the population pharmacokinetic study can be secondary to the objectives of the primary clinical study (in which case an add-on population pharmacokinetic protocol may be needed) or primary (when a stand-alone protocol is required). Having protocols for population pharmacokinetic studies is an integral part of 'good pharmacometric practice'. Real-time data assembly and analysis permit an ongoing evaluation of site compliance with the study protocol and provide the opportunity to correct violations of study procedures. Adequate policies and procedures should be in place for study blind maintenance. Real-time data assembly creates the opportunity for detecting and correcting errors in concentration-time data, drug administration history and covariate data. Population pharmacokinetic analyses may be undertaken in 3 interwoven steps: exploratory

  5. Pharmacokinetics and Safety of Caspofungin in Neonates and Infants Less than 3 Months of Age▿

    PubMed Central

    Sáez-Llorens, Xavier; Macias, Mercedes; Maiya, Padmanabha; Pineros, Juan; Jafri, Hasan S.; Chatterjee, Archana; Ruiz, Gloria; Raghavan, Janaki; Bradshaw, Susan K.; Kartsonis, Nicholas A.; Sun, Peng; Strohmaier, Kim M.; Fallon, Marissa; Bi, Sheng; Stone, Julie A.; Chow, Joseph W.

    2009-01-01

    Candida infections represent a major threat in neonatal intensive care units. This is the first prospective study to obtain caspofungin plasma levels and safety data for neonates and very young infants. Patients of <3 months of age receiving intravenous amphotericin B for documented or highly suspected candidiasis were enrolled in a single-dose (n = 6) or subsequent multiple-dose (n = 12) panel; all received caspofungin at 25 mg/m2 once daily as a 1-hour infusion. Caspofungin plasma levels were measured by high-performance liquid chromatography and compared to historical data from adults. Patient chronological ages ranged from 1 to 11 weeks, and weights ranged from 0.68 to 3.8 kg. Gestational ages ranged from 24 to 41 weeks. Geometric mean (GM) peak (C1 h) and trough (C24 h) caspofungin levels were 8.2 and 1.8 μg/ml, respectively, on day 1, and 11.1 and 2.4 μg/ml, respectively, on day 4. GM ratios for C1 h and C24 h for neonates/infants relative to adults receiving caspofungin at 50 mg/day were 1.07 and 1.36, respectively, on day 1, and 1.18 and 1.21, respectively, on day 4. Clinical and laboratory adverse events occurred in 17 (94%) and 8 (44%) patients, respectively. Five patients (28%) had serious adverse events, none of which were considered drug related. Caspofungin at 25 mg/m2 once daily was well tolerated in this group of neonates/infants of <3 months of age and appears to provide relatively similar plasma exposure to that obtained in adults receiving 50 mg/day. However, the small number of patients studied precludes any definitive recommendations about caspofungin dosing for this group comprising a broad range of ages and weights. PMID:19075070

  6. Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties

    PubMed Central

    Girolami, Federica; Persiani, Stefano

    2012-01-01

    Glucosamine is an amino monosaccharide and a natural constituent of glycosaminoglycans in articular cartilage. When administered exogenously, it is used for the treatment of osteoarthritis as a prescription drug or a dietary supplement. The latter use is mainly supported by its perception as a cartilage building block, but it actually exerts specific pharmacologic effects, mainly decreasing interleukin 1-induced gene expression by inhibiting the cytokine intracellular signaling cascade in general and nuclear factor-kappa B (NF-kB) activation in particular. As a whole, the use of glucosamine in the management of osteoarthritis is supported by the clinical trials performed with the original prescription product, that is, crystalline glucosamine sulfate. This is the stabilized form of glucosamine sulfate, while other formulations or different glucosamine salts (e.g. hydrochloride) have never been shown to be effective. In particular, long-term pivotal trials of crystalline glucosamine sulfate 1500 mg once daily have shown significant and clinically relevant improvement of pain and function limitation (symptom-modifying effect) in knee osteoarthritis. Continuous administration for up to 3 years resulted in significant reduction in the progression of joint structure changes compared with placebo as assessed by measuring radiologic joint space narrowing (structure-modifying effect). The two effects combined may suggest a disease-modifying effect that was postulated based on an observed decrease in the risk of undergoing total joint replacement in the follow up of patients receiving the product for at least 12 months in the pivotal trials. The safety of the drug was good in clinical trials and in the postmarketing surveillance. Crystalline glucosamine sulfate 1500 mg once daily is therefore recommended in the majority of clinical practice guidelines and was found to be cost effective in pharmacoeconomic analyses. Compared with other glucosamine formulations, salts, or

  7. 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

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

    2010-12-01

    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.

  8. Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety.

    PubMed

    Ido, Akio; Moriuchi, Akihiro; Numata, Masatsugu; Murayama, Toshinori; Teramukai, Satoshi; Marusawa, Hiroyuki; Yamaji, Naohisa; Setoyama, Hitoshi; Kim, Il-Deok; Chiba, Tsutomu; Higuchi, Shuji; Yokode, Masayuki; Fukushima, Masanori; Shimizu, Akira; Tsubouchi, Hirohito

    2011-05-08

    Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

  9. Pharmacokinetic evaluation of omeprazole suspension following oral administration in rats: effect of neutralization of gastric acid.

    PubMed

    Watanabe, K; Matsuka, N; Furuno, K; Eto, K; Kawasaki, H; Gomita, Y

    1996-08-01

    In order to evaluate a clinical use of omeprazole suspension, we examined the pharmacokinetics of omeprazole after oral administration in rats. Although the administration of omeprazole suspension buffered by NaHCO3 solution did not produce a significant increase in the area under the concentration-time curve (AUC) value compared with non-buffered group, the administration of NaHCO3 buffer immediately after dosing of omeprazole suspension buffered by NaHCO3 caused a significant increase in the AUC value. These results suggest that the NaHCO3 treatment following the administration of omeprazole buffered suspension effectively decreased the degradation of the compound by gastric acid. Therefore, the successive administratio