Statistical power calculations for mixed pharmacokinetic study designs using a population approach.

PubMed

Kloprogge, Frank; Simpson, Julie A; Day, Nicholas P J; White, Nicholas J; Tarning, Joel

2014-09-01

Simultaneous modelling of dense and sparse pharmacokinetic data is possible with a population approach. To determine the number of individuals required to detect the effect of a covariate, simulation-based power calculation methodologies can be employed. The Monte Carlo Mapped Power method (a simulation-based power calculation methodology using the likelihood ratio test) was extended in the current study to perform sample size calculations for mixed pharmacokinetic studies (i.e. both sparse and dense data collection). A workflow guiding an easy and straightforward pharmacokinetic study design, considering also the cost-effectiveness of alternative study designs, was used in this analysis. Initially, data were simulated for a hypothetical drug and then for the anti-malarial drug, dihydroartemisinin. Two datasets (sampling design A: dense; sampling design B: sparse) were simulated using a pharmacokinetic model that included a binary covariate effect and subsequently re-estimated using (1) the same model and (2) a model not including the covariate effect in NONMEM 7.2. Power calculations were performed for varying numbers of patients with sampling designs A and B. Study designs with statistical power >80% were selected and further evaluated for cost-effectiveness. The simulation studies of the hypothetical drug and the anti-malarial drug dihydroartemisinin demonstrated that the simulation-based power calculation methodology, based on the Monte Carlo Mapped Power method, can be utilised to evaluate and determine the sample size of mixed (part sparsely and part densely sampled) study designs. The developed method can contribute to the design of robust and efficient pharmacokinetic studies.

A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014-2017) and perspectives.

PubMed

Shi, Peiying; Lin, Xinhua; Yao, Hong

2018-05-01

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of 'integrated pharmacokinetics of TCMs' from 2014 to 2017 and the part of 'reverse pharmacokinetics in drug discovery from natural medicines' in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb-drug interactions and herb-herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.

[A prospective study of antipyrine pharmacokinetics in pregnancy].

PubMed

Asymbekova, G U

1995-01-01

Pharmacokinetics of a single dose of antipyrin (10 mg/kg) subjected to biotransformation at the expense of microsomal oxidation of its molecule in the liver was studied in 6 healthy nonpregnant women and in 24 women within the frames of a prospective follow-up starting from the early terms of gestation; 7 of these women developed edemas, proteinuria and/or hypertension in the course of follow-up. The results permit us consider that a test with a single antipyrin dose may be used as a marker to characterize drugs with similar metabolic transformations when used in pregnant women. The identity of pharmacokinetic regularities of antipyrin in samples of blood plasma and saliva permit the use of saliva as biological material for assessment of the metabolic profile of pregnant women. The problem of drug therapy in the third trimester is closely connected with specific features of pharmacokinetic profile detected by antipyrin test both in normal and complicated gestation. Our data evidence that the third trimester is characterized by special tension of the metabolic processes. A complicated course is associated with unambiguous changes in the metabolic activity of drugs, this necessitating special attention of a physician to drug dose.

Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

PubMed

Paliwal, Pankaj; Dash, Debabrata; Krishnamurthy, Sairam

2018-04-01

Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. All the pharmacokinetic parameters of piracetam including area under curve (AUC 0-24 ), maximum plasma concentration (C max ), time to reach the maximum plasma concentration (t max ), elimination half-life (t 1/2 ), volume of distribution (V z ), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC 0-2 ) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for

Studies on pharmacokinetic drug interaction potential of vinpocetine

USDA-ARS?s Scientific Manuscript database

Background: Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in literature. Due to increasing use of dietar...

Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

PubMed Central

Wojciechowski, Jessica; Mudge, Stuart; Upton, Richard N.; Foster, David J. R.

2017-01-01

ABSTRACT The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens. PMID:28052851

A COMPREHENSIVE INSIGHT ON OCULAR PHARMACOKINETICS

PubMed Central

Agrahari, Vibhuti; Mandal, Abhirup; Agrahari, Vivek; Trinh, Hoang My; Joseph, Mary; Ray, Animikh; Hadji, Hicheme; Mitra, Ranjana; Pal, Dhananjay; Mitra, Ashim K.

2017-01-01

Eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment model of ocular drug delivery has been developed for describing the absorption, distribution and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems and routes of administration are discussed including factors affecting intraocular bioavailability. Factors such as pre-corneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, drug metabolism renders ocular delivery challenging and elaborated in this manuscript. Several compartment models are discussed those are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations. PMID:27798766

Methodological issues in microdialysis sampling for pharmacokinetic studies.

PubMed

de Lange, E C; de Boer, A G; Breimer, D D

2000-12-15

Microdialysis is an in vivo technique that permits monitoring of local concentrations of drugs and metabolites at specific sites in the body. Microdialysis has several characteristics, which makes it an attractive tool for pharmacokinetic research. About a decade ago the microdialysis technique entered the field of pharmacokinetic research, in the brain, and later also in peripheral tissues and blood. Within this period much has been learned on the proper use of this technique. Today, it has outgrown its child diseases and its potentials and limitations have become more or less well defined. As microdialysis is a delicate technique for which experimental factors appear to be critical with respect to the validity of the experimental outcomes, several factors should be considered. These include the probe; the perfusion solution; post-surgery interval in relation to surgical trauma, tissue integrity and repeated experiments; the analysis of microdialysate samples; and the quantification of microdialysate data. Provided that experimental conditions are optimized to give valid and quantitative results, microdialysis can provide numerous data points from a relatively small number of individual animals to determine detailed pharmacokinetic information. An example of one of the added values of this technique compared with other in vivo pharmacokinetic techniques, is that microdialysis reflects free concentrations in tissues and plasma. This gives the opportunity to assess information on drug transport equilibration across membranes such as the blood-brain barrier, which already has provided new insights. With the progress of analytical methodology, especially with respect to low volume/low concentration measurements and simultaneous measurement of multiple compounds, the applications and importance of the microdialysis technique in pharmacokinetic research will continue to increase.

Patient acceptability and practical implications of pharmacokinetic studies in patients with advanced cancer.

PubMed

Dobbs, N A; Twelves, C J; Ramirez, A J; Towlson, K E; Gregory, W M; Richards, M A

1993-01-01

We have studied the practical implications and acceptability to patients of pharmacokinetic studies in 34 women receiving anthracyclines for advanced breast cancer. The following parameters were recorded: age, ECOG performance status, psychological state (Rotterdam Symptom Checklist), cytotoxic drug and dose, number of venepunctures for treatment and sampling, and time when the sampling cannula was removed. Immediately after finishing pharmacokinetic sampling, patients completed a questionnaire which revealed that (i) all patients understood sampling was for research, (ii) 35% of patients experienced problems with sampling, (iii) benefits from participation were perceived by 56% of patients. Of 20 patients later questioned after completion of their treatment course, 40% recalled difficulties with blood sampling. Factors identifying in advance those patients who tolerate pharmacokinetic studies poorly were not identified but the number of venepunctures should be minimised. Patients may also perceive benefits from 'non-therapeutic' research.

Pharmacokinetic study of anidulafungin in ICU patients with intra-abdominal candidiasis.

PubMed

Dupont, H; Massias, L; Jung, B; Ammenouche, N; Montravers, P

2017-05-01

Only limited pharmacokinetic data are available for anidulafungin in ICU patients, especially in patients treated for severe intra-abdominal infection (IAI). This was a prospective multicentre observational study in ICU patients with suspected yeast IAI. All patients received an intravenous loading dose of 200 mg of anidulafungin, followed by 100 mg/day. Thirteen blood samples were drawn between day 1 and day 5 for pharmacokinetic analysis. Samples were analysed by an HPLC-tandem MS method. Demographics and SAPS2 and SOFA scores were recorded. Fourteen patients with a median age (IQR) of 62 years (48-70) and with a mean BMI of 30.5 kg/m 2 were included from three centres; 57.1% were women. Their median (IQR) SAPS2 score was 54 (45-67) and their median (IQR) SOFA score was 8 (7-12). Six patients with community-acquired IAI and eight patients with nosocomial-acquired IAI were included. Twelve yeasts were isolated: six Candida albicans , two Candida glabrata , two Candida tropicalis , one Candida parapsilosis and one Candida krusei . Pharmacokinetic parameters were as follows [mean (% coefficient of variation)]: C max (mg/L) = 6.0 (29%); T max (h) = 1.6 (25.8%); C min (mg/L) = 3.2 (36.8%); AUC 0-24 (mg·h/L) = 88.9 (38.6%); t 1/2 (h) = 42.1 (68.2%); CL (L/h) = 1.2 (42.3%); and V (L) = 72.8 (87.8%). A two-compartment model best described the anidulafungin concentrations in the population pharmacokinetic study. The pharmacokinetic parameters of anidulafungin in critically ill ICU patients with complicated IAI are similar to those observed in the literature. However, an increased V and a longer t 1/2 were observed in this study. (EudraCT No. 2010-018695-25). © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data.

PubMed

Hopkins, Ashley M; Wojciechowski, Jessica; Abuhelwa, Ahmad Y; Mudge, Stuart; Upton, Richard N; Foster, David J R

2017-03-01

The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion ( P < 0.01) and then backward deletion ( P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability ( F ), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens. Copyright © 2017 American Society for Microbiology.

Pharmacokinetics, phenotype and product choice in haemophilia B: how to strike a balance?

PubMed

Berntorp, E; Dolan, G; Hermans, C; Laffan, M; Santagostino, E; Tiede, A

2014-11-01

At the 7th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) held in Brussels, Belgium, in February 2014, Pfizer sponsored a satellite symposium entitled: "Pharmacokinetics, phenotype and product choice in haemophilia B: How to strike a balance?" Co-chaired by Cedric Hermans (Cliniques Universitaires Saint Luc, Brussels, Belgium) and Mike Laffan (Imperial College, London, UK), the symposium provided an opportunity to debate whether pharmacokinetic (PK) parameters are good surrogates for clinical efficacy for haemophilia B in clinical practice, consider the perceptions and evidence of disease severity, and examine how these considerations can inform approaches to balancing the potential risks and benefits of the currently available treatment options for haemophilia B. PK parameters are routinely measured in clinical practice and are a requirement of regulatory bodies to demonstrate the clinical efficacy of products; however, the relationship between measured PK parameters and clinical efficacy is yet to be determined, an issue that was debated by Gerry Dolan (University Hospital, Queen's Medical Centre, Nottingham, UK) and Erik Berntorp (Lund University, Malmö Centre for Thrombosis and Haemostasis, Malmö, Sweden). Elena Santagostino (Universita degli Studi di Milano, Milano, Italy) reviewed how differing perceptions on the severity of haemophilia B compared with haemophilia A may have an impact on clinical decision-making. Finally, Andreas Tiede (Hannover Medical School, Hannover, Germany), examined the considerations for balancing the potential risks and benefits of the currently available treatment options for haemophilia B. Although the pathophysiology of haemophilia B has been widely studied and is largely understood, continued investigation and discussion around the optimal management course and appropriate therapeutic choice is warranted. © 2014 John Wiley & Sons Ltd.

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

PubMed

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

2016-12-01

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

A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.

PubMed

Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

2016-01-01

Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of

A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling

PubMed Central

Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

2016-01-01

Background Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients’ compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. Methods The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box–Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Results and Discussion Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box–Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry

PLAB and UK graduates' performance on MRCP(UK) and MRCGP examinations: data linkage study.

PubMed

McManus, I C; Wakeford, Richard

2014-04-17

To assess whether international medical graduates passing the two examinations set by the Professional and Linguistic Assessments Board (PLAB1 and PLAB2) of the General Medical Council (GMC) are equivalent to UK graduates at the end of the first foundation year of medical training (F1), as the GMC requires, and if not, to assess what changes in the PLAB pass marks might produce equivalence. Data linkage of GMC PLAB performance data with data from the Royal Colleges of Physicians and the Royal College of General Practitioners on performance of PLAB graduates and UK graduates at the MRCP(UK) and MRCGP examinations. Doctors in training for internal medicine or general practice in the United Kingdom. 7829, 5135, and 4387 PLAB graduates on their first attempt at MRCP(UK) Part 1, Part 2, and PACES assessments from 2001 to 2012 compared with 18,532, 14,094, and 14,376 UK graduates taking the same assessments; 3160 PLAB1 graduates making their first attempt at the MRCGP AKT during 2007-12 compared with 14,235 UK graduates; and 1411 PLAB2 graduates making their first attempt at the MRCGP CSA during 2010-12 compared with 6935 UK graduates. Performance at MRCP(UK) Part 1, Part 2, and PACES assessments, and MRCGP AKT and CSA assessments in relation to performance on PLAB1 and PLAB2 assessments, as well as to International English Language Testing System (IELTS) scores. MRCP(UK), MRCGP, and PLAB results were analysed as marks relative to the pass mark at the first attempt. PLAB1 marks were a valid predictor of MRCP(UK) Part 1, MRCP(UK) Part 2, and MRCGP AKT (r=0.521, 0.390, and 0.490; all P<0.001). PLAB2 marks correlated with MRCP(UK) PACES and MRCGP CSA (r=0.274, 0.321; both P<0.001). PLAB graduates had significantly lower MRCP(UK) and MRCGP assessments (Glass's Δ=0.94, 0.91, 1.40, 1.01, and 1.82 for MRCP(UK) Part 1, Part 2, and PACES and MRCGP AKT and CSA), and were more likely to fail assessments and to progress more slowly than UK medical graduates. IELTS scores correlated

PLAB and UK graduates’ performance on MRCP(UK) and MRCGP examinations: data linkage study

PubMed Central

Wakeford, Richard

2014-01-01

Objectives To assess whether international medical graduates passing the two examinations set by the Professional and Linguistic Assessments Board (PLAB1 and PLAB2) of the General Medical Council (GMC) are equivalent to UK graduates at the end of the first foundation year of medical training (F1), as the GMC requires, and if not, to assess what changes in the PLAB pass marks might produce equivalence. Design Data linkage of GMC PLAB performance data with data from the Royal Colleges of Physicians and the Royal College of General Practitioners on performance of PLAB graduates and UK graduates at the MRCP(UK) and MRCGP examinations. Setting Doctors in training for internal medicine or general practice in the United Kingdom. Participants 7829, 5135, and 4387 PLAB graduates on their first attempt at MRCP(UK) Part 1, Part 2, and PACES assessments from 2001 to 2012 compared with 18 532, 14 094, and 14 376 UK graduates taking the same assessments; 3160 PLAB1 graduates making their first attempt at the MRCGP AKT during 2007-12 compared with 14 235 UK graduates; and 1411 PLAB2 graduates making their first attempt at the MRCGP CSA during 2010-12 compared with 6935 UK graduates. Main outcome measures Performance at MRCP(UK) Part 1, Part 2, and PACES assessments, and MRCGP AKT and CSA assessments in relation to performance on PLAB1 and PLAB2 assessments, as well as to International English Language Testing System (IELTS) scores. MRCP(UK), MRCGP, and PLAB results were analysed as marks relative to the pass mark at the first attempt. Results PLAB1 marks were a valid predictor of MRCP(UK) Part 1, MRCP(UK) Part 2, and MRCGP AKT (r=0.521, 0.390, and 0.490; all P<0.001). PLAB2 marks correlated with MRCP(UK) PACES and MRCGP CSA (r=0.274, 0.321; both P<0.001). PLAB graduates had significantly lower MRCP(UK) and MRCGP assessments (Glass’s Δ=0.94, 0.91, 1.40, 1.01, and 1.82 for MRCP(UK) Part 1, Part 2, and PACES and MRCGP AKT and CSA), and were more likely to fail assessments

Optimal design in pediatric pharmacokinetic and pharmacodynamic clinical studies.

PubMed

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

2015-03-01

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

A Physiologically Based Pharmacokinetic Model for Pregnant Women to Predict the Pharmacokinetics of Drugs Metabolized Via Several Enzymatic Pathways.

PubMed

Dallmann, André; Ince, Ibrahim; Coboeken, Katrin; Eissing, Thomas; Hempel, Georg

2017-09-18

Physiologically based pharmacokinetic modeling is considered a valuable tool for predicting pharmacokinetic changes in pregnancy to subsequently guide in-vivo pharmacokinetic trials in pregnant women. The objective of this study was to extend and verify a previously developed physiologically based pharmacokinetic model for pregnant women for the prediction of pharmacokinetics of drugs metabolized via several cytochrome P450 enzymes. Quantitative information on gestation-specific changes in enzyme activity available in the literature was incorporated in a pregnancy physiologically based pharmacokinetic model and the pharmacokinetics of eight drugs metabolized via one or multiple cytochrome P450 enzymes was predicted. The tested drugs were caffeine, midazolam, nifedipine, metoprolol, ondansetron, granisetron, diazepam, and metronidazole. Pharmacokinetic predictions were evaluated by comparison with in-vivo pharmacokinetic data obtained from the literature. The pregnancy physiologically based pharmacokinetic model successfully predicted the pharmacokinetics of all tested drugs. The observed pregnancy-induced pharmacokinetic changes were qualitatively and quantitatively reasonably well predicted for all drugs. Ninety-seven percent of the mean plasma concentrations predicted in pregnant women fell within a twofold error range and 63% within a 1.25-fold error range. For all drugs, the predicted area under the concentration-time curve was within a 1.25-fold error range. The presented pregnancy physiologically based pharmacokinetic model can quantitatively predict the pharmacokinetics of drugs that are metabolized via one or multiple cytochrome P450 enzymes by integrating prior knowledge of the pregnancy-related effect on these enzymes. This pregnancy physiologically based pharmacokinetic model may thus be used to identify potential exposure changes in pregnant women a priori and to eventually support informed decision making when clinical trials are designed in this

Experimental design and efficient parameter estimation in preclinical pharmacokinetic studies.

PubMed

Ette, E I; Howie, C A; Kelman, A W; Whiting, B

1995-05-01

Monte Carlo simulation technique used to evaluate the effect of the arrangement of concentrations on the efficiency of estimation of population pharmacokinetic parameters in the preclinical setting is described. Although the simulations were restricted to the one compartment model with intravenous bolus input, they provide the basis of discussing some structural aspects involved in designing a destructive ("quantic") preclinical population pharmacokinetic study with a fixed sample size as is usually the case in such studies. The efficiency of parameter estimation obtained with sampling strategies based on the three and four time point designs were evaluated in terms of the percent prediction error, design number, individual and joint confidence intervals coverage for parameter estimates approaches, and correlation analysis. The data sets contained random terms for both inter- and residual intra-animal variability. The results showed that the typical population parameter estimates for clearance and volume were efficiently (accurately and precisely) estimated for both designs, while interanimal variability (the only random effect parameter that could be estimated) was inefficiently (inaccurately and imprecisely) estimated with most sampling schedules of the two designs. The exact location of the third and fourth time point for the three and four time point designs, respectively, was not critical to the efficiency of overall estimation of all population parameters of the model. However, some individual population pharmacokinetic parameters were sensitive to the location of these times.

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

PubMed

Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

2017-11-16

Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was

Stable isotope methodology in the pharmacokinetic studies of androgenic steroids in humans.

PubMed

Shinohara, Y; Baba, S

1990-04-01

The use of stable isotopically labeled steroids combined with gas chromatography/mass spectrometry (GC/MS) has found a broad application in pharmacologic studies. Initially, stable isotopically labeled steroids served as the ideal analytic internal standard for GC/MS analysis; however, their in vivo use has expanded and has proven to be a powerful pharmacokinetic tool. We have successfully used stable isotope methodology to study the pharmacokinetic/bioavailability of androgens. The primary advantage of the technique is that endogenous and exogenous steroids with the same basic structure can be differentiated by using stable isotopically labeled analogs. The method was used to examine the pharmacokinetics of testosterone and testosterone propionate, and to clarify the influence of endogenous testosterone. Another advantage of the isotope methods is that steroidal drugs can be administered concomitantly in two formulations (e.g., solution and solid dosage). A single set of blood samples serves to describe the time course of the formulations being compared. This stable isotope coadministration technique was used to estimate the relative bioavailability of 17 alpha-methyltestosterone.

Safer Schools in the UK--A Case Study

ERIC Educational Resources Information Center

Hayden, Carol; Holt, Amanda; Martin, Denise; Nee, Claire

2011-01-01

This article reports a research that is based on a European Safer Schools Partnership that included ten countries and specifically the UK case study which was located in London. The initiators of this partnership had been involved in early SSPs in the UK and the educationalists were very much focussed on work that would address problematic…

Pharmacokinetic study of Noni fruit extract.

PubMed

Issell, Brian F; Franke, Adrian; Fielding, Robert M

2008-01-01

Many different products containing Noni (Morinda citrifolia) fruit extracts are sold throughout the world for health restoration and maintenance. Despite a large business enterprise fueling Noni's popularity, there is a lack of standardization of products and no scientific evidence of Noni's clinical efficacy and safety. There is also no evidence to indicate an optimal therapeutic dose or dosing interval. In an initial volunteer, scopoletin was identified as a bioactive marker of Noni exposure and a candidate for product standardization and pharmacokinetic studies. Subsequently, capsules containing the whole freeze-dried fruit of Noni were orally administered to nine healthy volunteers (3 per group) at doses of 1,500 mg (3 × 500 mg), 2,000 mg (4 × 500 mg) and 2,500 mg (5 × 500 mg). Plasma and urine samples were obtained from each subject prior to dosing and at 0.5, 1, 2, 4 and 8 h after dosing. Concentrations of scopoletin were determined by HPLC with PDA (scanning at 200-700 nm) and MS detection. Scopoletin rapidly enters the plasma after Noni ingestion, maintaining levels in the range of 0.5 to 5 ng/mL for at least 8 h after dosing. Scopoletin bioavailability appears to be low, with significant intersubject variability. We conclude that scopoletin can be used as a relatively specific marker of Noni exposure in the blood and particularly in urine when its pharmacokinetics is considered appropriately.

Pharmacokinetics of oral amantadine in greyhound dogs.

PubMed

Norkus, C; Rankin, D; Warner, M; KuKanich, B

2015-06-01

This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs. © 2014 John Wiley & Sons Ltd.

Population Pharmacokinetic Analyses of Lithium: A Systematic Review.

PubMed

Methaneethorn, Janthima

2018-02-01

Even though lithium has been used for the treatment of bipolar disorder for several decades, its toxicities are still being reported. The major limitation in the use of lithium is its narrow therapeutic window. Several methods have been proposed to predict lithium doses essential to attain therapeutic levels. One of the methods used to guide lithium therapy is population pharmacokinetic approach which accounts for inter- and intra-individual variability in predicting lithium doses. Several population pharmacokinetic studies of lithium have been conducted. The objective of this review is to provide information on population pharmacokinetics of lithium focusing on nonlinear mixed effect modeling approach and to summarize significant factors affecting lithium pharmacokinetics. A literature search was conducted from PubMed database from inception to December, 2016. Studies conducted in humans, using lithium as a study drug, providing population pharmacokinetic analyses of lithium by means of nonlinear mixed effect modeling, were included in this review. Twenty-four articles were identified from the database. Seventeen articles were excluded based on the inclusion and exclusion criteria. A total of seven articles were included in this review. Of these, only one study reported a combined population pharmacokinetic-pharmacodynamic model of lithium. Lithium pharmacokinetics were explained using both one- and two-compartment models. The significant predictors of lithium clearance identified in most studies were renal function and body size. One study reported a significant effect of age on lithium clearance. The typical values of lithium clearance ranged from 0.41 to 9.39 L/h. The magnitude of inter-individual variability on lithium clearance ranged from 12.7 to 25.1%. Only two studies evaluated the models using external data sets. Model methodologies in each study are summarized and discussed in this review. For future perspective, a population pharmacokinetic

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

PubMed

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

2005-09-01

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

Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine

PubMed Central

Manda, Vamshi K.; Avula, Bharathi; Dale, Olivia R.; Chittiboyina, Amar G.; Khan, Ikhlas A.; Walker, Larry A.; Khan, Shabana I.

2015-01-01

Abstract Background Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in the literature. Due to increasing use of dietary supplements in combination with conventional drugs, the risk of adverse effects is on the rise. As a preliminary step to predict a possibility of drug interaction during concomitant use of vinpocetine and conventional drugs, this study was carried out to evaluate the effects of vinpocetine on three main regulators of pharmacokinetic drug interactions namely, cytochromes P450 (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR). Methods Inhibition of CYPs was evaluated by employing recombinant enzymes. The inhibition of P-gp was determined by calcein-AM uptake method in transfected and wild type MDCKII cells. Modulation of PXR activity was monitored through a reporter gene assay in HepG2 cells. Results Vinpocetine showed a strong inhibition of P-gp (EC50 8 μM) and a moderate inhibition of recombinant CYP3A4 and CYP2D6 (IC50 2.8 and 6.5 μM) with no activity towards CYP2C9, CYP2C19 and CYP1A2 enzymes. In HLM, competitive inhibition of CYP3A4 (IC50 54 and Ki 19 μM) and non-competitive inhibition of CYP2D6 (IC50 19 and Ki 26 μM) was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine (30 μM) while lower doses were ineffective. Conclusion Strong inhibition of P-gp by vinpocetine is indicative of a possibility of drug interactions by altering the pharmacokinetics of drugs, which are the substrates of P-gp. However, the effects on CYPs and PXR indicate that vinpocetine may not affect CYP-mediated metabolism of drugs, as the inhibitory concentrations are much greater than the expected plasma concentrations in humans. PMID:28930203

Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine.

PubMed

Manda, Vamshi K; Avula, Bharathi; Dale, Olivia R; Chittiboyina, Amar G; Khan, Ikhlas A; Walker, Larry A; Khan, Shabana I

2015-06-05

Background: Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in the literature. Due to increasing use of dietary supplements in combination with conventional drugs, the risk of adverse effects is on the rise. As a preliminary step to predict a possibility of drug interaction during concomitant use of vinpocetine and conventional drugs, this study was carried out to evaluate the effects of vinpocetine on three main regulators of pharmacokinetic drug interactions namely, cytochromes P450 (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR). Methods: Inhibition of CYPs was evaluated by employing recombinant enzymes. The inhibition of P-gp was determined by calcein-AM uptake method in transfected and wild type MDCKII cells. Modulation of PXR activity was monitored through a reporter gene assay in HepG2 cells. Results: Vinpocetine showed a strong inhibition of P-gp (EC 50 8 µM) and a moderate inhibition of recombinant CYP3A4 and CYP2D6 (IC 50 2.8 and 6.5 µM) with no activity towards CYP2C9, CYP2C19 and CYP1A2 enzymes. In HLM, competitive inhibition of CYP3A4 (IC 50 54 and K i 19 µM) and non-competitive inhibition of CYP2D6 (IC 50 19 and K i 26 µM) was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine (30 µM) while lower doses were ineffective. Conclusion: Strong inhibition of P-gp by vinpocetine is indicative of a possibility of drug interactions by altering the pharmacokinetics of drugs, which are the substrates of P-gp. However, the effects on CYPs and PXR indicate that vinpocetine may not affect CYP-mediated metabolism of drugs, as the inhibitory concentrations are much greater than the expected plasma concentrations in humans.

Comparative pharmacokinetic study of the main components of cortex fraxini after oral administration in normal and hyperuricemic rats.

PubMed

Wang, Yinan; Zhao, Min; Ye, Hao; Shao, Yizhen; Yu, Yongbo; Wang, Miao; Zhao, Chunjie

2017-08-01

Cortex Fraxini is an important traditional Chinese herbal medicine used for the treatment of gout and hyperuricemia. An efficient and rapid ultra-performance liquid chromatography mass spectrometry method was developed and validated for simultaneous quantitation of six coumarins (aesculin, fraxin, aesculetin, fraxetin, sopoletin and 7-hydroxycoumarin) in normal and hyperuricemic rats plasma after oral administration of Cortex Fraxini. The method could successfully be applied for pharmacokinetics studies. The pharmacokinetic behavior of six coumarins in normal and hyperuricemia rats plasma was determined. Results showed that, for some of analytes, the pharmacokinetic parameters (AUC 0-t , AUC 0-∞ , C max , T max and CL) were significantly different between normal and hyperuricemic rats. The different pharmacokinetic parameters might result from renal impairment or a change of metabolic enzymes in the pathological state. The pharmacokinetic study in pathological state could provide more useful information to guide the clinical use of traditional Chinese herbal medicine. Copyright © 2017 John Wiley & Sons, Ltd.

Pharmacokinetic Study of 7 Compounds Following Oral Administration of Fructus Aurantii to Depressive Rats

PubMed Central

Zhang, Xianhua; Han, Linran; Liu, Jin; Xu, Qiuyue; Guo, Yuxin; Zheng, Wan; Wang, Jian; Huang, Xi; Ren, Ping

2018-01-01

In the present study, the pharmacokinetics of multi-components (naringenin, nobiletin, meranzin hydrate, narirutin, naringin, hesperidin, and neohesperidin) were investigated in acute depressive rats following oral administration of Fructus Aurantii (Zhi-Qiao, ZQ) extract (20 g/kg). A rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established to quantitatively or qualitatively analyze the 7 absorbed ingredients in the plasma, hippocampus and cortex of acute depressive rats. Biological samples were separated on a 300SB-C18 column, and the 7 compounds were detected with sequential positive and negative ionization modes. Our results confirmed that ZQ has antidepressant effects by decreasing the immobility time. In addition, this validated method showed good linearity (r ≥ 0.9987), and the lower limits of quantification were 2.73–16.38 ng/mL for the 7 analytes. This method successfully determined the pharmacokinetics of the 7 compounds and separated two pairs of isomers in plasma of acute depressive rats following oral administration of ZQ extracts. The 7 active ingredients were also identified as marked compounds in target tissues and should be further examined in pharmacokinetic studies with acute depressive rats. So, pharmacokinetic compounds were precisely linked with the antidepressant effect of ZQ in our study. This relationship is well-understood and contributes to the application of Traditional Chinese Medicine (TCM). PMID:29556193

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

PubMed

Kusawake, Tomohiro; Keirns, James J; Kowalski, Donna; den Adel, Martin; Groenendaal-van de Meent, Dorien; Takada, Akitsugu; Ohtsu, Yoshiaki; Katashima, Masataka

2017-12-01

Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUC inf ) and C max . After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUC inf increased by about 90%. In the bioavailability study, AUC inf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUC inf almost doubling when amenamevir was administered with food. The concentration versus

[Pharmacokinetic study of six aconitine alkaloids in aconiti lateralis radix praeparata in beagle dogs].

PubMed

Xiao, Ri-Ping; Lai, Xiao-Ping; Zhao, Yai; Yu, Liang-Wen; Zhu, Yue-Lan; Li, Geng

2014-02-01

To study the pharmacokinetics characteristics of six Aconitum alkaloids aconitine (AC), mesaconitine (MA), hypaconitine (HA), benzoylaconine (BAC), benzoylmesaconine (BMA) and benzoylhypaconine (BHA) in beagle dogs. An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for simultaneous quantitation of six Aconitum alkaloids in beagle dog plasma after oral administration of Aconiti Lateralis Radix Praeparata decoction. UPLC/MS/MS system coupled with an electrospray ionization (ESI) source was performed in multiple-reaction monitoring (MRM) mode. Sample preparation was performed with solid-phase extraction(SPE) on a 3 mL HLB cartridge before the analysis. The separation was applied on a Waters C8 column (100 mm x 2.1 mm, 1.7 microm) and a gradient elution of methanol and 0.2% formic acid-water was used as mobile phase. The pharmacokinetic parameters were calculated by the results of the analysis through the DAS 2. 1 software (Drug and Statistics for Windows). The results showed that the fitting model for the six Aconitum alkaloids was the one-compartment model pharmacokinetics. The method is successfully used for the pharmacokinetic evaluation of the six Aconitum alkaloids in beagle dog plasma, it can help monitor the ADME/Tox process when taking Aconiti Lateralis Radix Praeparata by observing the pharmacokinetic process. The results provide a good reference for clinical treatment and safe application of Aconiti Lateralis Radix Praeparata.

A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients

PubMed Central

Alloway, R R; Sadaka, B; Trofe-Clark, J; Wiland, A; Bloom, R D

2012-01-01

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC0–12h and peak concentration (Cmax) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97–108%, p = 0.486) for AUC0–12h and 1.09 (90% CI 101–118%, p = 0.057) for Cmax. Mean (SD) C0 was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines. PMID:22759200

Disclosure of pharmacokinetic drug results to understand nonadherence.

PubMed

van der Straten, Ariane; Montgomery, Elizabeth T; Musara, Petina; Etima, Juliane; Naidoo, Sarita; Laborde, Nicole; Hartmann, Miriam; Levy, Lisa; Bennie, Thola; Cheng, Helen; Piper, Jeanna; Grossman, Cynthia I; Marrazzo, Jeanne; Mensch, Barbara

2015-10-23

In VOICE, a phase IIB trial of daily oral and vaginal tenofovir for HIV prevention, at least 50% of women receiving active products had undetectable tenofovir in all plasma samples tested. MTN-003D, an ancillary study using in-depth interviews (IDIs) and focus group discussions (FGDs), together with retrospective disclosure of plasma tenofovir pharmacokinetic results, explored adherence challenges during VOICE. We systematically recruited participants with pharmacokinetic data (median six plasma samples), categorized as low (0%, N = 79), inconsistent (1-74%, N = 28) or high (≥75%; N = 20) on the basis of frequency of tenofovir detection. Following disclosure of pharmacokinetic results, reactions were captured and adherence challenges systematically elicited; IDIs and FGDs were audio-recorded, transcribed, coded and thematically analysed. We interviewed 127 participants from South Africa, Uganda and Zimbabwe. The most common reactions to pharmacokinetic results included surprise (41%; low pharmacokinetic), acceptance (39%; inconsistent pharmacokinetic) and happiness (65%; high pharmacokinetic). On the basis of participants' explanations, we developed a typology of adherence patterns: noninitiation, discontinuation, misimplementation (resulting from visit-driven use, variable taking, modified dosing or regimen) and adherence. Fear of product side effects/harm was a frequent concern, fuelled by stories shared among participants. Although women with high pharmacokinetic levels reported similar concerns, several described strategies to overcome challenges. Women at all pharmacokinetic levels suggested real-time drug monitoring and feedback to improve adherence and reporting. Retrospective provision of pharmacokinetic results seemingly promoted candid discussions around nonadherence and study participation. The effect of real-time drug monitoring and feedback on adherence and accuracy of reporting should be evaluated in trials.

Expert scientific judgment and cancer risk assessment: a pilot study of pharmacokinetic data.

PubMed

Hawkins, N C; Graham, J D

1988-12-01

When high-dose tumor data are extrapolated to low doses, it is typically assumed that the dose of a carcinogen delivered to target cells is proportional to the dose administered to test animals, even at exposure levels below the experimental range. Since pharmacokinetic data are becoming available that in some cases question the validity of this assumption, risk assessors must decide whether to maintain the standard assumption. A pilot study of formaldehyde is reported that was undertaken to demonstrate how expert scientific judgment can help guide a controversial risk assessment where pharmacokinetic data are considered inconclusive. Eight experts on pharmacokinetic data were selected by a formal procedure, and each was interviewed personally using a structured interview protocol. The results suggest that expert scientific opinion is polarized in this case, a situation that risk assessors can respond to with a range of risk characterizations considered biologically plausible by the experts. Convergence of expert opinion is likely in this case of several specific research strategies ar executed in a competent fashion. Elicitation of expert scientific judgment is a promising vehicle for evaluating the quality of pharmacokinetic data, expressing uncertainty in risk assessment, and fashioning a research agenda that offers possible forging of scientific consensus.

[Pharmacokinetics of digoxin in hyperthyroidism. Effect of methimazole].

PubMed

Izbicka, Maria; Gasińska, Teresa; Dec, Renata

2010-01-01

Cardiovascular abnormalities may be the only manifestations of overt hyperthyroidism. In patients with heart failure and atrial fibrillation digoxin can be beneficial in controlling the symptoms and signs, but hyperthyroid patients show an impaired response or even resistance to digoxin treatment. The aim of the study is to establish: 1. Are there any differences in the pharmacokinetics of a single oral dose of digoxin between hypertyroid and euthyroid patients? 2. Does simultaneous administration of digoxin and methimazole affect the pharmacokinetics of a single oral dose of dogoxin? 3. Does methimazole-induced euthyroidism change the pharmacokinetics of a single oral dose of digoxin? The subject of the study were 28 patients with hyperthyroidism and 15 healthy persons. We evaluated the pharmacokinetics of a single oral dose of digoxin. Moreover we evaluated pharmacokinetics of a single dose of digoxin after simultaneous administration of digoxin and methimazole in 12 patients and 12 methimazole treated patients werere-assessed once they had become euthyroid. Hyperthyroid patients showed significantly lower serum digoxin concentrations, shorter T1/2 beta and a significantly smaller area under the concentration curve (AUC) that the control group. Administration of methimazole did not affect digoxin pharmacokinetics. In hyperthyroid patients: 1. the pharmacokinetics of a single oral dose of digoxin does differ from that observed in healthy subjects. 2.methimazole do not alter digoxin pharmacokinetics.

Model selection for clustering of pharmacokinetic responses.

PubMed

Guerra, Rui P; Carvalho, Alexandra M; Mateus, Paulo

2018-08-01

Pharmacokinetics comprises the study of drug absorption, distribution, metabolism and excretion over time. Clinical pharmacokinetics, focusing on therapeutic management, offers important insights towards personalised medicine through the study of efficacy and toxicity of drug therapies. This study is hampered by subject's high variability in drug blood concentration, when starting a therapy with the same drug dosage. Clustering of pharmacokinetics responses has been addressed recently as a way to stratify subjects and provide different drug doses for each stratum. This clustering method, however, is not able to automatically determine the correct number of clusters, using an user-defined parameter for collapsing clusters that are closer than a given heuristic threshold. We aim to use information-theoretical approaches to address parameter-free model selection. We propose two model selection criteria for clustering pharmacokinetics responses, founded on the Minimum Description Length and on the Normalised Maximum Likelihood. Experimental results show the ability of model selection schemes to unveil the correct number of clusters underlying the mixture of pharmacokinetics responses. In this work we were able to devise two model selection criteria to determine the number of clusters in a mixture of pharmacokinetics curves, advancing over previous works. A cost-efficient parallel implementation in Java of the proposed method is publicly available for the community. Copyright © 2018 Elsevier B.V. All rights reserved.

Pharmacokinetics and Pharmacodynamics in Space

NASA Technical Reports Server (NTRS)

Putcha, Lakshmi; Cintron, Nitza M.

1990-01-01

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

Euthanasia method for mice in rapid time-course pulmonary pharmacokinetic studies.

PubMed

Schoell, Adam R; Heyde, Bruce R; Weir, Dana E; Chiang, Po-Chang; Hu, Yiding; Tung, David K

2009-09-01

To develop a means of euthanasia to support rapid time-course pharmacokinetic studies in mice, we compared retroorbital and intravenous lateral tail vein injection of ketamine-xylazine with regard to preparation time, utility, tissue distribution, and time to onset of euthanasia. Tissue distribution and time to onset of euthanasia did not differ between administration methods. However, retroorbital injection could be performed more rapidly than intravenous injection and was considered to be a technically simple and superior alternative for mouse euthanasia. Retroorbital ketamine-xylazine, CO(2) gas, and intraperitoneal pentobarbital then were compared as euthanasia agents in a rapid time-point pharmacokinetic study. Retroorbital ketamine-xylazine was the most efficient and consistent of the 3 methods, with an average time to death of approximately 5 s after injection. In addition, euthanasia by retroorbital ketamine-xylazine enabled accurate sample collection at closely spaced time points and satisfied established criteria for acceptable euthanasia technique.

Pharmacokinetic Studies of Sustained-Release Depot of Dexamethasone in Beagle Dogs.

PubMed

Blizzard, Charles; Desai, Ankita; Driscoll, Arthur

2016-11-01

To examine the pharmacokinetic characteristics of sustained-release dexamethasone depots in two separate canine studies. Dexamethasone depots loaded with a clinically representative (0.4 mg) dose (DEXTENZA™; Ocular Therapeutix) or an elevated (0.7 mg) dose were inserted into the canaliculi of beagle eyes (n = 37 and n = 34, respectively). Tear fluid was collected for pharmacokinetic analysis of dexamethasone in both studies at predetermined time points. Explanted 0.4 mg depots were collected weekly to measure remaining drug level. Clinical observations and ophthalmic examinations were performed in both studies at each visit. The 0.4 mg depots released a median 308 μg by day 15 and tapered to complete drug release by day 28. Median dexamethasone tear fluid concentrations in the 0.4 mg study group decreased from 2,805 ng/mL at day 7 to 0 ng/mL on day 28. Median dexamethasone tear fluid concentrations in the 0.7 mg study group decreased from 4,370 ng/mL at 6 h post insertion to 830 ng/mL on day 35. Mean ± standard deviation intraocular pressures in the 0.4 and 0.7 mg study groups were 20.7 ± 2.8 and 19.0 ± 4.1 mmHg at baseline, respectively, and demonstrated no meaningful change (20.5 ± 3.0 and 20.6 ± 2.9 mmHg, respectively) over the studies' durations. No ocular toxicities were attributed to the dexamethasone depot. Sustained-release dexamethasone produced no identifiable ocular toxicity in this animal model, and pharmacokinetics demonstrated a sustained and tapered drug release over 28 days at a 0.4 mg dose and exceeded 35 days at a 0.7 mg dose.

A randomized pharmacokinetic study of generic tacrolimus versus reference tacrolimus in kidney transplant recipients.

PubMed

Alloway, R R; Sadaka, B; Trofe-Clark, J; Wiland, A; Bloom, R D

2012-10-01

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC(0-12h) and peak concentration (C(max) ) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC(0-12h) and 1.09 (90% CI 101-118%, p = 0.057) for C(max) . Mean (SD) C(0) was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Population pharmacokinetics of aripiprazole in healthy Korean subjects.

PubMed

Jeon, Ji-Young; Chae, Soo-Wan; Kim, Min-Gul

2016-04-01

Aripiprazole is widely used to treat schizophrenia and bipolar disorder. This study aimed to develop a combined population pharmacokinetic model for aripiprazole in healthy Korean subjects and to identify the significant covariates in the pharmacokinetic variability of aripiprazole. Aripiprazole plasma concentrations and demographic data were collected retrospectively from previous bioequivalence studies that were conducted in Chonbuk National University Hospital. Informed consent was obtained from subjects for cytochrome P450 (CYP) genotyping. The population pharmacokinetic parameters of aripiprazole were estimated using nonlinear mixed-effect modeling with first-order conditional estimation with interaction method. The effects of age, sex, weight, height, and CYP genotype were assessed as covariates. A total of 1,508 samples from 88 subjects in three bioequivalence studies were collected. The two-compartment model was adopted, and the final population model showed that the CYP2D6 genotype polymorphism, height and weight significantly affect aripiprazole disposition. The bootstrap and visual predictive check results were evaluated, showing that the accuracy of the pharmacokinetic model was acceptable. A population pharmacokinetic model of aripiprazole was developed for Korean subjects. CYP2D6 genotype polymorphism, weight, and height were included as significant factors affecting aripiprazole disposition. The population pharmacokinetic parameters of aripiprazole estimated in the present study may be useful for individualizing clinical dosages and for studying the concentration-effect relationship of the drug.

SaMpling Antibiotics in Renal Replacement Therapy (SMARRT): an observational pharmacokinetic study in critically ill patients.

PubMed

Roberts, Jason A; Choi, Gordon Y S; Joynt, Gavin M; Paul, Sanjoy K; Deans, Renae; Peake, Sandra; Cole, Louise; Stephens, Dianne; Bellomo, Rinaldo; Turnidge, John; Wallis, Steven C; Roberts, Michael S; Roberts, Darren M; Lassig-Smith, Melissa; Starr, Therese; Lipman, Jeffrey

2016-03-01

Optimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality. We designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient's blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients' demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics. Using the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT. Australian New Zealand Clinical Trial Registry ( ACTRN12613000241730 ) registered 28 February 2013.

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

PubMed

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

2010-05-01

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

Image Guided Biodistribution and Pharmacokinetic Studies of Theranostics

PubMed Central

Ding, Hong; Wu, Fang

2012-01-01

Image guided technique is playing an increasingly important role in the investigation of the biodistribution and pharmacokinetics of drugs or drug delivery systems in various diseases, especially cancers. Besides anatomical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), molecular imaging strategy including optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) will facilitate the localization and quantization of radioisotope or optical probe labeled nanoparticle delivery systems in the category of theranostics. The quantitative measurement of the bio-distribution and pharmacokinetics of theranostics in the fields of new drug/probe development, diagnosis and treatment process monitoring as well as tracking the brain-blood-barrier (BBB) breaking through by high sensitive imaging method, and the applications of the representative imaging modalities are summarized in this review. PMID:23227121

Pharmacokinetic Studies of Chinese Medicinal Herbs Using an Automated Blood Sampling System and Liquid Chromatography-mass Spectrometry.

PubMed

Wu, Yu-Tse; Wu, Ming-Tsang; Lin, Chia-Chun; Chien, Chao-Feng; Tsai, Tung-Hu

2012-01-01

The safety of herbal products is one of the major concerns for the modernization of traditional Chinese medicine, and pharmacokinetic data of medicinal herbs guide us to design the rational use of the herbal formula. This article reviews the advantages of the automated blood sampling (ABS) systems for pharmacokinetic studies. In addition, three commonly used sample preparative methods, protein precipitation, liquid-liquid extraction and solid-phase extraction, are introduced. Furthermore, the definition, causes and evaluation of matrix effects in liquid chromatography-mass spectrometry (LC/MS) analysis are demonstrated. Finally, we present our previous works as practical examples of the application of ABS systems and LC/MS for the pharmacokinetic studies of Chinese medicinal herbs.

Pharmacokinetics of tilmicosin in beef cattle following intravenous and subcutaneous administration.

PubMed

Lombardi, K R; Portillo, T; Hassfurther, R; Hunter, R P

2011-12-01

The intravenous pharmacokinetic profile of tilmicosin is yet to be achieved because of the cardiovascular effects of tilmicosin. This study summarizes two pharmacokinetic studies that provided complete pharmacokinetic profile of tilmicosin in cattle. The first study was a pharmacokinetic study of tilmicosin in beef calves dosed by i.v. infusion over 5 h. The second study was a subcutaneous (s.c.) pharmacokinetic study comparing the pharmacokinetic profile of tilmicosin in light (approximately 170 kg) and heavy (approximately 335 kg) beef cattle and comparing the labeled dose range of 10 or 20 mg/kg dose. The data from the two different studies were used to calculate bioavailability values, which support the assumption that tilmicosin is 100% bioavailable in cattle. The results from the second study showed that the weight of an animal when administered tilmicosin does not have a significant effect on exposure, but did demonstrate that doubling the dose of tilmicosin administered doubles the systemic exposure to tilmicosin. © 2011 Blackwell Publishing Ltd.

Euthanasia Method for Mice in Rapid Time-Course Pulmonary Pharmacokinetic Studies

PubMed Central

Schoell, Adam R; Heyde, Bruce R; Weir, Dana E; Chiang, Po-Chang; Hu, Yiding; Tung, David K

2009-01-01

To develop a means of euthanasia to support rapid time-course pharmacokinetic studies in mice, we compared retroorbital and intravenous lateral tail vein injection of ketamine–xylazine with regard to preparation time, utility, tissue distribution, and time to onset of euthanasia. Tissue distribution and time to onset of euthanasia did not differ between administration methods. However, retroorbital injection could be performed more rapidly than intravenous injection and was considered to be a technically simple and superior alternative for mouse euthanasia. Retroorbital ketamine–xylazine, CO2 gas, and intraperitoneal pentobarbital then were compared as euthanasia agents in a rapid time-point pharmacokinetic study. Retroorbital ketamine–xylazine was the most efficient and consistent of the 3 methods, with an average time to death of approximately 5 s after injection. In addition, euthanasia by retroorbital ketamine–xylazine enabled accurate sample collection at closely spaced time points and satisfied established criteria for acceptable euthanasia technique. PMID:19807971

Microanalysis and preliminary pharmacokinetic studies of a sulfated polysaccharide from Laminaria japonica

NASA Astrophysics Data System (ADS)

Zhang, Wenjing; Sun, Delin; Zhao, Xia; Jin, Weihua; Wang, Jing; Zhang, Quanbin

2016-01-01

A rapid, sensitive and reproducible high performance liquid chromatography (HPLC) method with post-column fluorescence derivatization has been developed to determine the amount of low-molecular-weight sulfated polysaccharide (GFS) in vivo. The metabolism of GFS has been shown to fit a two component model following its administration by intravenous injection, and its pharmacokinetic parameters were determined to be as follows: half-time of distribution phase ( t 1/2α)=11.24±2.93 min, half-time of elimination phase ( t 1/2β)=98.20±25.78 min, maximum concentration ( C max)=110.53 μg/mL and peak time ( T max)=5 min. The pharmacokinetic behavior of GFS was also investigated following intragastric administration. However, the concentration of GFS found in serum was too low for detection, and GFS could only be detected for up to 2 h after intragastric administration (200 mg/kg body weight). Thus, the bioavailability of GFS was low following intragastric administration because of the metabolism of GFS. In conclusion, HPLC with postcolumn derivatization could be used for quantitative microanalysis and pharmacokinetic studies to determine the presence of polysaccharides in the serum following intravenous injection.

Longitudinal Comparison of Thyroxine Pharmacokinetics Between Pregnant and Nonpregnant Women: A Stable Isotope Study

PubMed Central

Soldin, Offie P.; Soldin, Steven J.; Vinks, Alexander A.; Younis, Islam; Landy, Helain J.

2013-01-01

The treatment of maternal hypothyroidism presents clinicians with a unique challenge, because dosing regimens previously developed and validated for nonpregnant women cannot be easily extrapolated to dosing in pregnancy. Thyroid hormone requirement increases by 20% to 40% early during pregnancy, persisting throughout gestation. Accordingly, women with treated hypothyroidism need to increase their levothyroxine dose to prevent maternal hypothyroidism and the associated impaired cognitive development and increased fetal mortality. We investigated the pharmacokinetic properties of levothyroxine during pregnancy through the use of a novel, traceable form of levothyroxine. The objective was to conduct a longitudinal study to determine whether levothyroxine pharmacokinetics differ in the pregnant versus nonpregnant state. We used a unique 13C-levothyroxine-tracer method to distinguish between endogenous and exogenous levothyroxine and studied the pharmacokinetics of a single oral dose of levothyroxine using tandem mass spectrometry. Moreover, we were able to detect single dose amounts of the drug, in picogram/mL concentrations. The area under the curve was 23.0 ng*h/mL in pregnancy and 14.8 ng*h/mL in nonpregnant women (P < 0.03) with median serum half-lives of 32.1 hours and 24.1 hours, respectively (P < 0.04). Further research involves the measurement of free thyroxine on these samples using tandem mass spectrometry. Future work should focus on the mechanisms responsible for the gestational differences in pharmacokinetics and whether these should necessitate dose schedule changes in pregnancy. PMID:20962709

[Pharmacokinetic studies of flomoxef in the neonatal field].

PubMed

Kimura, K; Miyano, T; Shimomura, H

1991-11-01

Flomoxef (FMOX), a new broad spectrum oxacephem antibiotic, was studied in the neonatal field and the pharmacokinetic results obtained are summarized below. 1. Serum concentrations of FMOX after dosages of 20 mg/kg via 1 hour drip infusion were 21.8 +/- 7.59 micrograms/ml, 15.4 +/- 4.35 micrograms/ml, 4.3 +/- 2.88 micrograms/ml at 1, 2 and 5 hours after administration, respectively, and T 2/1 (beta)'s averaged 2.08 +/- 1.01 hours. 2. Urinary excretion rates were 53.38 +/- 16.94% in the first 7 hours after administration.

[Research progress on current pharmacokinetic evaluation of Chinese herbal medicines].

PubMed

Li, Guofu; Zhao, Haoru; Yang, Jin

2011-03-01

In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction.

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

Lack of a Pharmacokinetic Interaction Between Saxagliptin and Dapagliflozin in Healthy Subjects: A Randomized Crossover Study.

PubMed

Vakkalagadda, Blisse; Lubin, Susan; Reynolds, Laurie; Liang, Dan; Marion, Alan S; LaCreta, Frank; Boulton, David W

2016-08-01

This single-dose, open-label, randomized, 3-period, 3-treatment crossover drug-drug interaction study was conducted to evaluate differences in the pharmacokinetic properties of saxagliptin and dapagliflozin when coadministered. Healthy subjects (N = 42) were randomized to receive saxagliptin 5 mg alone, dapagliflozin 10 mg alone, or saxagliptin 5 mg plus dapagliflozin 10 mg coadministered; there was a washout period of ≥6 days between treatments. Serial blood samples for determining saxagliptin, 5-hydroxy saxagliptin (5-OH saxagliptin; major active metabolite) and dapagliflozin plasma concentrations and pharmacokinetic parameters were collected before and up to 60 hours after the dose. No interaction was to be concluded if the 90% CIs for the geometric mean ratios of the combination compared with each drug given alone for Cmax and AUCinf were within 0.80 to 1.25. The results indicated that dapagliflozin had no effect on the pharmacokinetic properties of saxagliptin, 5-OH saxagliptin, or saxagliptin total active moiety and vice versa. The 90% CIs for Cmax and AUCinf for all comparisons were contained entirely within the 0.80 to 1.25 equivalence intervals. Other pharmacokinetic parameters (apparent oral clearance or half-life) of saxagliptin or dapagliflozin were similar when each medicine was administered alone or when coadministered. No safety profile or tolerability findings of concern were observed during the study. All adverse events were mild, and no serious adverse events were reported. These data indicate that coadministration of saxagliptin and dapagliflozin exhibits no pharmacokinetic interaction and is well tolerated. ClinicalTrials.gov identifier: NCT01662999. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

[Impact of ECMO on drugs pharmacokinetics].

PubMed

Hasni, Nesrine; Lemaitre, Florian; Fernandez, Christine; Combes, Alain; Farinotti, Robert

2011-01-01

Extracorporeal membrane oxygenation (ECMO) is a life support system used in the treatment of patients of all ages with severe respiratory or cardiorespiratory failure. Despite the intensive use of drugs in the treatment of patients on ECMO, few studies have been conducted to determine the impact of this device on the pharmacokinetics of drugs. Publications in this field have shown pharmacokinetics changes resulting in an increase in volume of distribution of drugs and/or decreased clearance with consequent increase of their half-life. Reduced plasma concentrations of some drugs due to their adsorption on the different components of the circuit further complicates the determination of pharmacokinetic parameters of patients treated by ECMO. The literature published up to now on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment. However, more research is needed to identify dosage strategies for this patient population. © 2011 Société Française de Pharmacologie et de Thérapeutique.

IS Curriculum Career Tracks: A UK Study

ERIC Educational Resources Information Center

Stefanidis, Angelos; Fitzgerald, Guy; Counsell, Steve

2013-01-01

Purpose: The purpose of this paper is to present the results of a comprehensive study on the specialisations or career tracks supported by the Information Systems (IS) curriculum in the UK. Design/methodology/approach: The study utilises the recently published IS curriculum guidelines (IS 2010) to develop a method for ranking the career tracks of…

Clarification of contraceptive drug pharmacokinetics in obesity☆

PubMed Central

Jusko, William J.

2017-01-01

Related to concerns about the role of obesity in the efficacy of contraceptive drugs, a review of the literature was carried out in regard to the pharmacokinetics of ethinyl estradiol and various progestins given by various routes of administration. Most studies show that obese women exhibit modestly lower plasma concentrations of these drugs (circa 30%) when given the same doses as normal-weight women. While the mechanism is uncertain, precedence in the literature suggests that this is due to body weight-related differences in metabolism rates. Confusing in some of the literature is that a few studies have reported erroneously calculated pharmacokinetic parameters after multiple dosing of oral contraceptives. A demonstration of appropriate pharmacokinetic methodology is provided. PMID:27542520

An Introduction to ESERO-UK, the UK Space Education Office

ERIC Educational Resources Information Center

Clements, Allan; Mather, Edward

2012-01-01

This article introduces the UK branch of the European Space Education Resource Office (ESERO-UK), also known as the UK Space Education Office. It is a teaching project designed to use space to enthuse primary and secondary students to study science, technology, engineering and mathematics (STEM) subjects. The office is funded by the European Space…

Pharmacokinetics & Neurophysiology

ERIC Educational Resources Information Center

Davis, Andrew S.; Salpekar, Jay A.

2009-01-01

Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

The studies of anti-inflammatory and analgesic activities and pharmacokinetics of Oxytropis falcate Bunge extraction after transdermal administration in rats.

PubMed

Chen, Zhi-peng; Qu, Min-ming; Chen, Hong-xuan; Liu, Dan; Xiao, Yan-yu; Chen, Jun; Lu, Tu-lin; Cai, Bao-chang

2011-04-01

The aim of this study was to evaluate the activities of anti-inflammatory and analgesic of the total flavonoids extraction from Oxytropis falcate Bunge (FEO) after transdermal administration. The pharmacokinetics and absolute bioavailability of FEO in rat, furthermore, was studied. Firstly, the anti-inflammatory and analgesic effects of the FEO were studied by xylene-induced ear edema, adjuvant-induced joint inflammation law in rats, acetic acid-induced writhing and hot-plate tests in mice. Secondly, we developed a sensitive and specific HPLC method to analyze 2', 4'-dihydroxychalcone (TFC, the mainly ingredient of FEO) in rat plasma to study the pharmacokinetic of TEC. The results showed FEO has anti-inflammatory and analgesic property in a dose-dependent manner, and that the high dose group (90.6 mg/kg) of FEO appeared more significantly effective than the positive drug. From the pharmacokinetic studies of TFC in rats, we got the main pharmacokinetic parameters of TFC, providing a basis for the future studies in clinic. Copyright © 2010 Elsevier B.V. All rights reserved.

Pharmacokinetics and bioequivalence study of two brands of loxoprofen tablets in healthy volunteers.

PubMed

Jhee, Ok Hwa; Lee, Min Ho; Shaw, Leslie M; Lee, Seo Eun; Park, Jin Hee; Kang, Ju Seop

2007-01-01

The aims of this study were to assess the pharmacokinetics and bioequivalence of two brands of loxoprofen (CAS 80832-23-6) 60 mg tablets in healthy male volunteers. The several pharmacokinetic parameters were evaluated after an oral administration after an overnight fast according to a single dose, two-sequence, and cross-over randomized design with a 1-week washout interval. Serial blood samples were collected throughout 10 h after administration of the reference and test drug. Plasma was analyzed by validated HPLC with UV detection. Several pharmacokinetic parameters, including AUC(infnity), AUC(t), C(max), T(max), T1/2, and Ke were determined from blood concentrations of both formulations. AUC(t), AUC(infinity) and C(max) were evaluated for bioequivalence after log-transformation of data using ANOVA with 90% confidence interval level. The parametric 90% confidence intervals of AUC(t), AUC(infinity), and C(max) were 90.13-106.34%, 91.43-106.94%, and 91.17-108.53%, respectively. All of the tested parameters were within the acceptable range of 80-125%. Based on these statistical considerations, it was concluded that the test drug was bioequivalent to the reference drug.

International Students' Perceptions of Service Quality in the UK Banking Sector: An Exploratory Study

ERIC Educational Resources Information Center

Bond, Christopher; Hsu, Marc Ting-Chun

2011-01-01

This study reviews and evaluates international students' perceptions of UK banks. The specific research objectives were to identify international students' expectations and perceptions of service quality from UK banks and to assess the quality GAP or dissonance between these. A total of 297 international students studying in the UK responded to…

Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine.

PubMed

Tfelt-Hansen, Peer; Ågesen, Frederik Nybye; Pavbro, Agniezka; Tfelt-Hansen, Jacob

2017-05-01

In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum plasma concentration was reported in 248 single-dose and 115 steady-state pharmacokinetic studies, and the area under the plasma concentration-time curve was reported in 299 single-dose studies and 112 steady-state pharmacokinetic studies. For each study, the coefficient of variation was calculated for maximum plasma concentration and area under the plasma concentration-time curve, and we divided the drug variability into two categories; high variability, coefficient of variation >40%, or low or moderate variability, coefficient of variation <40%. Based on the area under the plasma concentration-time curve in steady-state studies, the following drugs have high pharmacokinetic variability: propranolol in 92% (33/36), metoprolol in 85% (33/39), and amitriptyline in 60% (3/5) of studies. The following drugs have low or moderate variability: atenolol in 100% (2/2), valproate in 100% (15/15), topiramate in 88% (7/8), and naproxen and candesartan in 100% (2/2) of studies. For drugs with low or moderate pharmacokinetic variability, treatment can start without initial titration of doses, whereas titration is used to possibly enhance tolerability of topiramate and amitriptyline. The very high pharmacokinetic variability of metoprolol and propranolol can result in very high plasma concentrations in a small minority of patients, and those drugs should therefore be titrated up from a low initial dose, depending mainly on the occurrence of adverse events.

Using dried blood spot sampling to improve data quality and reduce animal use in mouse pharmacokinetic studies.

PubMed

Wickremsinhe, Enaksha R; Perkins, Everett J

2015-03-01

Traditional pharmacokinetic analysis in nonclinical studies is based on the concentration of a test compound in plasma and requires approximately 100 to 200 μL blood collected per time point. However, the total blood volume of mice limits the number of samples that can be collected from an individual animal-often to a single collection per mouse-thus necessitating dosing multiple mice to generate a pharmacokinetic profile in a sparse-sampling design. Compared with traditional methods, dried blood spot (DBS) analysis requires smaller volumes of blood (15 to 20 μL), thus supporting serial blood sampling and the generation of a complete pharmacokinetic profile from a single mouse. Here we compare plasma-derived data with DBS-derived data, explain how to adopt DBS sampling to support discovery mouse studies, and describe how to generate pharmacokinetic and pharmacodynamic data from a single mouse. Executing novel study designs that use DBS enhances the ability to identify and streamline better drug candidates during drug discovery. Implementing DBS sampling can reduce the number of mice needed in a drug discovery program. In addition, the simplicity of DBS sampling and the smaller numbers of mice needed translate to decreased study costs. Overall, DBS sampling is consistent with 3Rs principles by achieving reductions in the number of animals used, decreased restraint-associated stress, improved data quality, direct comparison of interanimal variability, and the generation of multiple endpoints from a single study.

Using Dried Blood Spot Sampling to Improve Data Quality and Reduce Animal Use in Mouse Pharmacokinetic Studies

PubMed Central

Wickremsinhe, Enaksha R; Perkins, Everett J

2015-01-01

Traditional pharmacokinetic analysis in nonclinical studies is based on the concentration of a test compound in plasma and requires approximately 100 to 200 µL blood collected per time point. However, the total blood volume of mice limits the number of samples that can be collected from an individual animal—often to a single collection per mouse—thus necessitating dosing multiple mice to generate a pharmacokinetic profile in a sparse-sampling design. Compared with traditional methods, dried blood spot (DBS) analysis requires smaller volumes of blood (15 to 20 µL), thus supporting serial blood sampling and the generation of a complete pharmacokinetic profile from a single mouse. Here we compare plasma-derived data with DBS-derived data, explain how to adopt DBS sampling to support discovery mouse studies, and describe how to generate pharmacokinetic and pharmacodynamic data from a single mouse. Executing novel study designs that use DBS enhances the ability to identify and streamline better drug candidates during drug discovery. Implementing DBS sampling can reduce the number of mice needed in a drug discovery program. In addition, the simplicity of DBS sampling and the smaller numbers of mice needed translate to decreased study costs. Overall, DBS sampling is consistent with 3Rs principles by achieving reductions in the number of animals used, decreased restraint-associated stress, improved data quality, direct comparison of interanimal variability, and the generation of multiple endpoints from a single study. PMID:25836959

Pharmacokinetic Interaction Study of Ranitidine and Daijokito in Healthy Volunteers

PubMed Central

Endo, Yusuke; Ishihara, Yoshitaka; Tsuno, Satoshi; Matsuda, Akiko; Qian, Weibin; Miura, Norimasa; Hasegawa, Junichi

2016-01-01

Background Ranitidine is a histamine 2 receptor antagonist, and daijokito is a Kampo (Chinese herbal medicine as practiced in Japan) formula, which is traditionally used for treating constipation and digestive trouble. Previous study demonstrated that daijokito significantly affected the pharmacokinetics of ranitidine in rats; however, the doses of ranitidine and daijokito in that study were higher than in clinical practice. Therefore, we examined the pharmacokinetic interaction between ranitidine and daijokito in clinical practice doses in healthy volunteers. Methods This was a randomized, open label, two-period crossover study in healthy volunteers (n = 7). Volunteers received administrations of either a single dose of ranitidine 300 mg, or ranitidine 300 mg in combination with daijokito extract granules 2.5 g. Plasma concentrations of ranitidine were measured over 12 h by LC/MS/MS method. Results Plasma concentrations of ranitidine were lower with co-administration of daijokito compared with ranitidine alone. Co-administration of daijokito significantly decreased ranitidine area under the plasma concentration-time curve from 0 to 12 h (AUC0–12) and maximum plasma concentration (Cmax) with geometric mean (GM) ratio [90% confidence interval (CI)] for AUC0–12 of 0.609 (0.449, 0.826) and Cmax of 0.515 (0.345, 0.771). Conclusion Co-administration of ranitidine with daijokito resulted in a significant decrease in plasma level of ranitidine in healthy volunteers. PMID:27493481

Pharmacokinetics in pregnancy; clinical significance.

PubMed

Koren, Gideon

2011-01-01

In pharmacokinetics drug absorption, distribution, clearance, and bioequivalence are usually considered, but during pregnancy the most important variable is adherence or compliance. Pharmacokinetic changes during pregnancy that may lead to changes in maternal drug use are described through presentation of cases highlighting the relevance of these changes. Non-invasive methods of pharmacokinetic analysis, such as determining concentrations of drug in hair, are now being tested and used.Pharmacokinetics are important, but one needs to consider the entire pregnant state and its circumstances when treating women. One treats people, not a "volume of distribution" or a drug level. Therapy should be individualized as much as possible, addressing kinetic changes in the context of dynamic alterations and the effects of underlying medical conditions. To ensure that women are not orphaned from advances in drug therapy, much more research is needed into the determinants of pharmacokinetic and pharmacodynamic changes in pregnancy.

Pharmacokinetics of a once-daily extended-release formulation of pramipexole in healthy male volunteers: three studies.

PubMed

Jenner, Peter; Könen-Bergmann, Michael; Schepers, Cornelia; Haertter, Sebastian

2009-11-01

Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily. These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation. Three Phase I studies were conducted, all in healthy adult men aged study, 7 prototypes of a once-daily ER formulation with various release properties, including rate and pH dependence, were compared with the IR formulation taken 3 times daily to identify the optimal pharmacokinetic resemblance based on predefined criteria derived from plasma AUC(0-24h), C(max), and C(min). In the second study, a level A in vitro/in vivo correlation (IVIVC) suitable for predicting an entire in vivo bioavailability time course based on in vitro dissolution was established and validated, and the single-dose pharmacokinetics of the optimal ER formulation identified in the first study were analyzed for food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375-4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs). The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC(0-24h,ss) of 17.4 ng.h/mL (vs 16.0 ng.h/mL for the IR formulation), C(max,ss) of 0.967 ng/mL (vs 1.09 ng/mL), and C(min,ss) of 0.455 ng/mL (vs 0.383 ng/mL). For single

[The enantioselective pharmacokinetic study of desvenlafaxine sustained release tablet in Chinese healthy male volunteers after oral administration].

PubMed

Chen, Yin-xia; Du, Jiang-bo; Zhang, Yi-fan; Chen, Xiao-yan; Zhong, Da-fang

2015-04-01

A chiral LC-MS/MS method for the simultaneous analysis of desvenlafaxine (DVS) enantiomers in human plasma was developed and applied to a pharmacokinetic study on 12 Chinese healthy volunteers. d6-Desvenlafaxine was used as internal standard (IS). Chromatographic separation was performed on the Astec Chirobiotic V chiral column (150 mm x 4.6 mm, 5 μm). The assay was linear over the concentration range of 0.500-150 ng x mL(-1) for both enantiomers (r2 > 0.99). The method was successfully applied to a stereoselective pharmacokinetic study of 100 mg desvenlafaxine sustained release tablets on 12 Chinese healthy volunteers under fasting conditions. The results showed that the pharmacokinetic parameters were similar to both enantiomers in Chinese healthy volunteers. The AUC(0-t), and C(max) of the two enantiomers were about 1.5 times higher than those of blacks and whites reported in the literature.

Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations.

PubMed

Walter, Carmen; Knothe, Claudia; Lötsch, Jörn

2016-07-01

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

[Pharmacokinetics study of amoxicillin sodium clavulanate potassium (10:1) injection in healthy volunteers].

PubMed

Miao, Jia; Nan, Feng; Shen, Qi; Qin, Yong-Ping; Wang, Ying; Yu, Qin; Zheng, Li; Liang, Mao-Zhi

2013-03-01

To study the pharmacokinetics of amoxicillin sodium clavulanate potassium (10:1) injection with different single doses intravenous infusion and one dose repeated intravenous injection in healthy volunteers for guiding the rational clinical regimen. Using infusion pump constantly intravenous dripping in 30 min, 4 mL blood samples were collected before and after the administration at 10 min, 20 min, 30 min, 45 min, and 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 10 h. The plasma concentrations of amoxicillin and clavulanate were detected by high performance liquid chromatography- mass spectrometry/mass spectrometry method. The pharmacokinetic parameters were calculated by DAS2.0.1 software. The dispositions of amoxicillin and clavulanate matched three or two compartment model with the weight coefficient 1/cc. To avoid the biases caused by compartment model fitting, the pharmacokinetic parameters were statistical moment parameters of non-compartment model. The peak concentrations, the areas under curve, the half-lifes and the clearances after single injections of 0. 55 g, 1.1 g and 2.2 g indicated that both amoxillin and clavulanate had linear dynamics characteristics. After 1.1 g single dose and multiple doses infusion, the pharmacokinetic parameters of amoxicillin and clavulanate were close respectively, and the trough concentrations before the 7th to 13th administration were lower than the detection limitation, which implied that the previous administration had cleared out before the next administration, and no accumulation happened after multiple doses. The amoxicillin sodium clavulanate potassium (10:1) injection possesses the linear kinetics. The dosage regimen of 1.1 g Q8h intravenous infusion could meet the needs of clinical therapy.

Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

PubMed

Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

2017-06-01

Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

PubMed

Oosten, Astrid W; Abrantes, João A; Jönsson, Siv; de Bruijn, Peter; Kuip, Evelien J M; Falcão, Amílcar; van der Rijt, Carin C D; Mathijssen, Ron H J

2016-04-01

Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.

Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients.

PubMed

Guan, Xiao-Feng; Li, Dai-Yang; Yin, Wen-Jun; Ding, Jun-Jie; Zhou, Ling-Yun; Wang, Jiang-Lin; Ma, Rong-Rong; Zuo, Xiao-Cong

2018-02-01

Diltiazem is a benzothiazepine calcium blocker and widely used in renal transplant patients since it improves the level of tacrolimus or cyclosporine A concentration. Several population pharmacokinetic (PopPK) models had been established for cyclosporine A and tacrolimus but no specific PopPK model was established for diltiazem. The aim of the study is to develop a PopPK model for diltiazem in renal transplant recipients and provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study. Patients received tacrolimus as primary immunosuppressant agent after renal transplant and started administration of diltiazem 90 mg twice daily on 5th day. The concentration of diltiazem at 0, 0.5, 1, 2, 8, and 12 h was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Genotyping for CYP3A4*1G, CYP3A5*3, and MDR1 3435 was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). 25 covariates were considered in the stepwise covariate model (SCM) building procedure. One-compartment structural pharmacokinetic model with first-order absorption and elimination was used to describe the pharmacokinetic characteristics of diltiazem. Total bilirubin (TBIL) influenced apparent volume of distribution (V/F) of diltiazem in the forward selection. The absorption rate constant (K a ), V/F, and apparent oral clearance (CL/F) of the final population pharmacokinetic (PopPK) model of diltiazem were 1.96/h, 3550 L, and 92.4 L/h, respectively. A PopPK model of diltiazem is established in Chinese renal transplant recipients and it will provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study.

Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia.

PubMed

Kuang, Yun; Zhang, Ran-Ran; Pei, Qi; Tan, Hong-Yi; Guo, Cheng-Xian; Huang, Jie; Xiang, Yu-Xia; Ouyang, Wen; Duan, Kai-Ming; Wang, Sai-Ying; Yang, Guo-Ping

2015-12-01

The application of dexmedetomidine in patient sedation is generally accepted, though its clinical application is limited because of the lack of information detailing the specific properties among diverse populations of patients. The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between elderly and young patients during spinal anesthesia. 34 subjects (elderly group: n = 15; young group: n = 19) with spinal anesthesia were enrolled in the present study following the inclusion/exclusion criteria detailed below. All subjects received intravenous infusion of dexmedetomidine with a loading dose of 0.5 µg x kg⁻¹ for 10 minutes and a maintenance dose of 0.5 µg x kg⁻¹ x h⁻¹ for 50 minutes. Plasma concentrations of dexmedetomidine were detected by the HPLC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software. There was no significant difference between the elderly and young subjects in major pharmacokinetic parameters. There was a marked gender difference in the Cmax (peak plasma concentration) and tmax (time to reach Cmax) between genders in elderly subjects, though in this cohort the other pharmacokinetic parameters were not significantly different. In the young subjects there were no noteworthy variations between genders in pharmacokinetic parameters. There was no significant difference between the two groups in BISAUC(0-t) (the area under the bispectral index-time curve from time 0 to t hours), BISmin (the minimum value of the bispectral index after drug delivery), and or tmin-BIS (bispectral index for the minimum value of time). SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), and SpO₂(pulse oxygen saturation) developed substantive differences in a time-dependent manner, but there were no statistically significant differences in these four indicators in the time*group at three time points (1 hour, 2 hours, and 3 hours after drug

A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation.

PubMed

Ding, Junjie; Wang, Yi; Lin, Weiwei; Wang, Changlian; Zhao, Limei; Li, Xingang; Zhao, Zhigang; Miao, Liyan; Jiao, Zheng

2015-03-01

Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy. A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM(®) software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models. The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model. The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

[LC-MS/MS method for determination of tripterine in plasma： pharmacokinetic study in Beagles].

PubMed

Zhang, Jun; Liu, Shi-Jia; Hu, Jie-Hui; Xu, Mei-Juan; Liu, Zi-Xiu; Zhou, Ling; Ju, Wen-Zheng

2016-07-01

To establish a LC-MS/MS method for determination of tripterine in Beagle plasma and study its pharmacokinetics after oral administration of tripterygium tablet. Plasma samples were extracted with dichloromethane and separated on a Phenomenex Luna C₈ (2.0 mm×50 mm, 3 μm) column with methanol-acetonitrile isopropanol(1∶1)-1‰formic acid (15∶55 ∶30) as the mobile phase. Tripterine ([M+H] ⁺, m/z 451.3/201.1) and internal standard prednisolone ([M+H] ⁺, m/z 361.1/147.1) were monitored in multiple reaction monitoring (MRM). The concentration-time curves were simulated by drug and statistic software 1.0 and the pharmacokinetic parameters were calculated. There was a good linear relationship between peak area ratio and concentration of tripterine and internal standard prednisolone within range of 0.680 0-136.0 μg•L⁻¹. The limit of quantitation was 0.680 0 μg•L⁻¹ and the intra- and inter-day precision was within 6.15%. The absolute recovery rate was between 50.42% to 51.65%. The concentration-time curves were consistent with the one-compartment model(w=1/cc). The main pharmacokinetic parameters after a single dose were as follows： Cmax (35.64±9.540) μg •L⁻¹,Tmax(2.62±0.69) h,T1/2(2.93±0.29) h, CL (0.308±0.056) L•kg⁻¹•h⁻¹, AUC0-12 (131.16±31.94) μg•L•h⁻¹, AUC0-∞ (142.83±37.57) μg•L•h⁻¹. The established LC-MS/MS method was proved to be sensitive, accurate and convenient, suitable for the pharmacokinetic study of Tripterygium tablet in Beagle dogs. Copyright© by the Chinese Pharmaceutical Association.

Pharmacokinetics of ginkgolide B injection in beagle dogs.

PubMed

Song, H; Bu, F; Wei, C; Yuan, G; Liu, X; Wang, B; Guo, R

2012-12-01

A liquid chromatography-mass spectrometry method was developed, validated, and applied to the pharmacokinetic study with doses of 0.68, 2.73 and 10.92 mg/kg of ginkgolide B in beagle dogs after intravenous infusion.An aliquot of blood samples were -collected, separated and quantitatively analyzed by liquid chromatography-mass spectrometry method with mobile phase of acetonitrile-0.02% ammonia solution (33:67, v/v) at a flow rate of 0.8 mL/min on the UltimateTM XB-C18 column (5 μm, 4.6×150 mm).The method was sensitive, accurate and convenient, and can be used for the determination of ginkgolide B in beagle dogs. The Cmax and AUC0-∞ of GB increased with dose escalation, but ANOVA analyses showed that no significant difference was observed in other pharmacokinetic parameters between different doses.An LC/MS method was developed with good sensitivity, reproducibility and specificity. In the pharmacokinetic study of GB in beagle dogs, linear pharmacokinetics was found at doses from 0.62 to 10.92 mg/kg after a single-dose intravenous infusion. Gender differences were not observed in the pharmacokinetics of GB. © Georg Thieme Verlag KG Stuttgart · New York.

Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

NASA Astrophysics Data System (ADS)

Sudhakar, Beeravelli; Krishna, Mylangam Chaitanya; Murthy, Kolapalli Venkata Ramana

2016-01-01

The aim of the present study was to formulate and evaluate the ritonavir-loaded stealth liposomes by using 32 factorial design and intended to delivered by parenteral delivery. Liposomes were prepared by ethanol injection method using 32 factorial designs and characterized for various physicochemical parameters such as drug content, size, zeta potential, entrapment efficiency and in vitro drug release. The optimization process was carried out using desirability and overlay plots. The selected formulation was subjected to PEGylation using 10 % PEG-10000 solution. Stealth liposomes were characterized for the above-mentioned parameters along with surface morphology, Fourier transform infrared spectrophotometer, differential scanning calorimeter, stability and in vivo pharmacokinetic studies in rats. Stealth liposomes showed better result compared to conventional liposomes due to effect of PEG-10000. The in vivo studies revealed that stealth liposomes showed better residence time compared to conventional liposomes and pure drug solution. The conventional liposomes and pure drug showed dose-dependent pharmacokinetics, whereas stealth liposomes showed long circulation half-life compared to conventional liposomes and pure ritonavir solution. The results of statistical analysis showed significance difference as the p value is (<0.05) by one-way ANOVA. The result of the present study revealed that stealth liposomes are promising tool in antiretroviral therapy.

Anti-cancer, pharmacokinetic and biodistribution studies of cremophor el free alternative paclitaxel formulation.

PubMed

Jain, Subheet K; Utreja, Puneet; Tiwary, Ashok K; Mahajan, Mohit; Kumar, Nikhil; Roy, Partha

2014-01-01

The aim of the present investigation is to determine the in vivo potential of previously developed and optimized Cremophor EL free paclitaxel (CF-PTX) formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate. CF-PTX was found to have drug loading of 6 mg/ml similar to Cremophor EL based marketed paclitaxel formulation. In the present study, intracellular uptake, repeated dose 28 days sub-acute toxicity, anti-cancer activity, biodistribution and pharmacokinetic studies were conducted to determine in vivo performance of CF-PTX formulation in comparison to marketed paclitaxel formulation. Intracellular uptake of CF-PTX was studied using A549 cells by fluorescence activated cell sorting assay (FACS) and fluorescence microscopy. In vivo anti-cancer activity of CF-PTX was evaluated using Ehrlich ascites carcinoma (EAC) model in mice followed by biodistribution and pharmacokinetic studies. FACS investigation showed that fluorescence marker acridine orange (AO) solution showed only 19.8±1.1% intracellular uptake where as significantly higher uptake was observed in the case of AO loaded CF-PTX formulation (85.4±2.3%). The percentage reduction in tumor volume for CF-PTX (72.5±2.3%) in EAC bearing mice was found to be significantly (p<0.05) higher than marketed formulation (58.6±2.8%) on 14th day of treatment. Pharmacokinetic and biodistribution studies showed sustained plasma concentration of paclitaxel depicted by higher mean residence time (MRT; 18.2±1.8 h) and elimination half life (12.8±0.6 h) with CF-PTX formulation as compared to marketed formulation which showed 4.4±0.2 h MRT and 3.6±0.4 h half life. The results of the present study demonstrated better in vivo performance of CF-PTX and this formulation appears to be a promising carrier for sustained and targeted delivery of paclitaxel.

Results of Phase II Pharmacokinetic Study of Levetiracetam for Prevention of Posttraumatic Epilepsy

PubMed Central

Klein, Pavel; Herr, Daniel; Pearl, Phillip L.; Natale, JoAnne; Levine, Zachary; Nogay, Claude; Sandoval, Fabian; Trzcinsky, Stacey; Atabaki, Shireen M.; Tsuchida, Tammy; van den Anker, John; Soldin, Steven J.; He, Jianping; McCarter, Robert

2015-01-01

Levetiracetam (LEV) has anti-epileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients are unknown. We report pharmacokinetics of TBI subjects ≥6 years with high PTE risk treated with LEV 55 mg/kg/day orally, nasogastrically or intravenously for 30 days starting ≤8 hours after injury in a phase 2 safety and pharmacokinetic study. 41 subjects (26 adults, 15 children) were randomized to PK studies on treatment days 3 and 30. 36/41 randomized subjects underwent PK study on treatment day 3, and 24/41 subjects on day 30. On day 3, mean Tmax was 2.2 hours, Cmax 60.2 μg/ml and AUC 403.7 h*/μg/ml. Tmax was longer in the elderly than in children and non-elderly adults (5.96 h vs. 1.5 h and 1.8 h, p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4 h*/μg/ml vs. 461.4 and 450.2, p=0.08). Cmax trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4 μg/ml vs. 59 and 48.2, p=0.07). AUC for n.g. and i.v. administrations were 79% and 88% of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55 mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies. PMID:22771222

Pharmacokinetic Profile of a 2-Month Dose Regimen of Aripiprazole Lauroxil: A Phase I Study and a Population Pharmacokinetic Model.

PubMed

Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Wehr, Angela Y; Weiden, Peter J; von Moltke, Lisa

2017-07-01

Aripiprazole lauroxil (AL) is a long-acting injectable medication approved for the treatment of schizophrenia. Current AL regimens are 441 mg, 662 mg, and 882 mg administered monthly (every 4 weeks [q4wk]), or 882 mg administered every 6 weeks (q6wk). We examined the feasibility of a 2-month (every 8 weeks [q8wk]) dosing interval of AL in a phase I open-label pharmacokinetic study investigating AL 1064 mg administered q8wk for 24 weeks, followed by 20 weeks of safety and pharmacokinetic measurements (ClinicalTrials.gov ID: NCT02320032). Second, a population pharmacokinetic model (referred to as the 2MPopPK model) was generated using data collected from the present trial, as well as data obtained from earlier studies. The phase I study included patients with schizophrenia or schizoaffective disorder maintained on an oral antipsychotic (n = 140) who were assigned to one of three groups: AL 441 mg q4wk, AL 882 mg q6wk, or AL 1064 mg q8wk, with a total of seven, five, or four injections administered, respectively. No oral aripiprazole lead-in supplementation was administered and patients continued on maintenance oral antipsychotics. Pharmacokinetic samples were collected at various time points during the 24-week study period and the 20-week follow-up period. Plasma concentrations obtained from the phase I study were analyzed using non-compartmental methods. Additionally, the data were combined with data collected from prior studies to develop the 2MPopPK model. Following the final injection of AL in the phase I study, maximum aripiprazole concentrations were achieved 24.4-35.2 days after the last dose and persisted for the duration of the study. The mean C avg,ss values were 125.8 ng/ml, 131.1 ng/ml, and 140.7 ng/ml for the 441 mg q4wk, 882 mg q6wk, and 1064 mg q8wk doses, respectively. The mean elimination half-life of aripiprazole following the last dose was 53.9 days for the 1064 mg dose, 55.1 days for the 882 mg dose, and 57.2 days for

Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

PubMed

Wiebe, Sabrina; Schnell, David; Külzer, Raimund; Gansser, Dietmar; Weber, Anne; Wallenstein, Gudrun; Halabi, Atef; Conrad, Anja; Wind, Sven

2017-06-01

Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30-59 mL/min/1.73 m 2 and 15-29 mL/min/1.73 m 2 , respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC last ) and maximum plasma concentration (C max ) between subjects with renal impairment and healthy matched controls. Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUC last and C max , was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUC last for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3-213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28-39 % for moderate impairment, 34-42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

[Features of bemithyl pharmacokinetics upon inhalation administration].

PubMed

Kurpiakova, A F; Geĭbo, D S; Bykov, V N; Nikiforov, A S

2014-01-01

A comparative study of bemithyl pharmacokinetics was carried out upon its inhalation, intragastric and intravenous administration. The main drug metabolites were identified and the pharmacokinetic parameters were calculated. The obtained results suggest that the inhalation administration of bemithyl is a promising replacement for oral administration, which is related to high bioavailability of the drug and the absence of the effect of "first pass" through the liver.

Pharmacokinetics and Tissue Distribution Study of Chlorogenic Acid from Lonicerae Japonicae Flos Following Oral Administrations in Rats

PubMed Central

Zhou, Yulu; Zhou, Ting; Pei, Qi; Liu, Shikun; Yuan, Hong

2014-01-01

Chlorogenic acid (ChA) is proposed as the major bioactive compounds of Lonicerae Japonicae Flos (LJF). Forty-two Wistar rats were randomly divided into seven groups to investigate the pharmacokinetics and tissue distribution of ChA, via oral administration of LJF extract, using ibuprofen as internal standard, employing a high performance liquid chromatography in conjunction with tandem mass spectrometry. Analytes were extracted from plasma samples and tissue homogenate by liquid–liquid extraction with acetonitrile, separated on a C 18 column by linear gradient elution, and detected by electrospray ionization mass spectrometry in negative selected multiple reaction monitoring mode. Our results successfully demonstrate that the method has satisfactory selectivity, linearity, extraction recovery, matrix effect, precision, accuracy, and stability. Using noncompartment model to study pharmacokinetics, profile revealed that ChA was rapidly absorbed and eliminated. Tissue study indicated that the highest level was observed in liver, followed by kidney, lung, heart, and spleen. In conclusion, this method was suitable for the study on pharmacokinetics and tissue distribution of ChA after oral administration. PMID:25140190

Metabolic and pharmacokinetic studies of scutellarin in rat plasma, urine, and feces.

PubMed

Xing, Jian-feng; You, Hai-sheng; Dong, Ya-lin; Lu, Jun; Chen, Si-ying; Zhu, Hui-fang; Dong, Qian; Wang, Mao-yi; Dong, Wei-hua

2011-05-01

To study the metabolic and pharmacokinetic profile of scutellarin, an active component from the medical plant Erigeron breviscapus (Vant) Hand-Mazz, and to investigate the mechanisms underlying the low bioavailability of scutellarin though oral or intravenous administration in rats. HPLC method was developed for simultaneous detection of scutellarin and scutellarein (the aglycone of scutellarin) in rat plasma, urine and feces. The in vitro metabolic stability study was carried out in rat liver microsomes from different genders. After a single oral dose of scutellarin (400 mg/kg), the plasma concentrations of scutellarin and scutellarein in female rats were significantly higher than in male ones. Between the female and male rats, significant differences in AUC, t(max2) and C(max2) for scutellarin were found. The pharmacokinetic parameters of scutellarin in the urine also showed significant gender differences. After a single oral dose of scutellarin (400 mg/kg), the total percentage excretion of scutellarein in male and female rats was 16.5% and 8.61%, respectively. The total percentage excretion of scutellarin and scutellarein in the feces was higher with oral administration than with intravenous administration. The in vitro t(1/2) and CL(int) value for scutellarin in male rats was significantly higher than that in female rats. The results suggest that a large amount of ingested scutellarin was metabolized into scutellarein in the gastrointestinal tract and then excreted with the feces, leading to the extremely low oral bioavailability of scutellarin. The gender differences of pharmacokinetic parameters of scutellarin and scutellarein are due to the higher CL(int) and lower absorption in male rats.

Metabolic and pharmacokinetic studies of scutellarin in rat plasma, urine, and feces

PubMed Central

Xing, Jian-feng; You, Hai-sheng; Dong, Ya-lin; Lu, Jun; Chen, Si-ying; Zhu, Hui-fang; Dong, Qian; Wang, Mao-yi; Dong, Wei-hua

2011-01-01

Aim: To study the metabolic and pharmacokinetic profile of scutellarin, an active component from the medical plant Erigeron breviscapus (Vant) Hand-Mazz, and to investigate the mechanisms underlying the low bioavailability of scutellarin though oral or intravenous administration in rats. Methods: HPLC method was developed for simultaneous detection of scutellarin and scutellarein (the aglycone of scutellarin) in rat plasma, urine and feces. The in vitro metabolic stability study was carried out in rat liver microsomes from different genders. Results: After a single oral dose of scutellarin (400 mg/kg), the plasma concentrations of scutellarin and scutellarein in female rats were significantly higher than in male ones. Between the female and male rats, significant differences in AUC, tmax2 and Cmax2 for scutellarin were found. The pharmacokinetic parameters of scutellarin in the urine also showed significant gender differences. After a single oral dose of scutellarin (400 mg/kg), the total percentage excretion of scutellarein in male and female rats was 16.5% and 8.61%, respectively. The total percentage excretion of scutellarin and scutellarein in the feces was higher with oral administration than with intravenous administration. The in vitro t1/2 and CLint value for scutellarin in male rats was significantly higher than that in female rats. Conclusion: The results suggest that a large amount of ingested scutellarin was metabolized into scutellarein in the gastrointestinal tract and then excreted with the feces, leading to the extremely low oral bioavailability of scutellarin. The gender differences of pharmacokinetic parameters of scutellarin and scutellarein are due to the higher CLint and lower absorption in male rats. PMID:21516133

Application of a novel liquid chromatography/tandem mass spectrometry method for the determination of antazoline in human plasma: Result of ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study.

PubMed

Giebułtowicz, Joanna; Piotrowski, Roman; Baran, Jakub; Kułakowski, Piotr; Wroczyński, Piotr

2016-05-10

Antazoline is a first-generation antihistaminic agent with antiarrhythmic quinidine-like properties. In some countries, it is widely used for termination of cardiac arrhythmias, especially atrial fibrillation (AF). However, no human pharmacokinetic studies have been conducted with intravenous antazoline. The aim of our study was to develop and validate a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the determination of antazoline in human plasma: the ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study. Antazoline was extracted from plasma using liquid-liquid extraction. The concentration of the analyte was measured by LC-MS/MS with xylometazoline as an internal standard. The method was validated for linearity, precision, accuracy, stability (freeze/thaw stability, stability in autosampler, short and long term stability), dilution integrity and matrix effect. The analyzed validation criteria were fulfilled. The method was applied to a pharmacokinetic study involving 10 healthy volunteers. Following a single intravenous dose of antazoline mesylate (100 mg), the plasma concentration profile showed a relative fast elimination with a terminal elimination half-life of 2.29 h. A relatively high volume of distribution was observed (Vss=315 L). The values of mean residence time (MRT∞), area under the curve (AUC∞) and clearance were 3.45 h, 0.91 mg h L(-1) and 80.5 L h(-1), respectively. One volunteer showed significant differences in pharmacokinetic parameters. In conclusion, the proposed new LC-MS/MS method was successfully used for the first time for the determination of antazoline in human plasma. Copyright © 2016 Elsevier B.V. All rights reserved.

Heritability of metoprolol and torsemide pharmacokinetics.

PubMed

Matthaei, J; Brockmöller, J; Tzvetkov, M V; Sehrt, D; Sachse-Seeboth, C; Hjelmborg, J B; Möller, S; Halekoh, U; Hofmann, U; Schwab, M; Kerb, R

2015-12-01

Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated. © 2015 American Society for Clinical Pharmacology and Therapeutics.

Real-Time Microfluidic Blood-Counting System for PET and SPECT Preclinical Pharmacokinetic Studies.

PubMed

Convert, Laurence; Lebel, Réjean; Gascon, Suzanne; Fontaine, Réjean; Pratte, Jean-François; Charette, Paul; Aimez, Vincent; Lecomte, Roger

2016-09-01

Small-animal nuclear imaging modalities have become essential tools in the development process of new drugs, diagnostic procedures, and therapies. Quantification of metabolic or physiologic parameters is based on pharmacokinetic modeling of radiotracer biodistribution, which requires the blood input function in addition to tissue images. Such measurements are challenging in small animals because of their small blood volume. In this work, we propose a microfluidic counting system to monitor rodent blood radioactivity in real time, with high efficiency and small detection volume (∼1 μL). A microfluidic channel is built directly above unpackaged p-i-n photodiodes to detect β-particles with maximum efficiency. The device is embedded in a compact system comprising dedicated electronics, shielding, and pumping unit controlled by custom firmware to enable measurements next to small-animal scanners. Data corrections required to use the input function in pharmacokinetic models were established using calibrated solutions of the most common PET and SPECT radiotracers. Sensitivity, dead time, propagation delay, dispersion, background sensitivity, and the effect of sample temperature were characterized. The system was tested for pharmacokinetic studies in mice by quantifying myocardial perfusion and oxygen consumption with (11)C-acetate (PET) and by measuring the arterial input function using (99m)TcO4 (-) (SPECT). Sensitivity for PET isotopes reached 20%-47%, a 2- to 10-fold improvement relative to conventional catheter-based geometries. Furthermore, the system detected (99m)Tc-based SPECT tracers with an efficiency of 4%, an outcome not possible through a catheter. Correction for dead time was found to be unnecessary for small-animal experiments, whereas propagation delay and dispersion within the microfluidic channel were accurately corrected. Background activity and sample temperature were shown to have no influence on measurements. Finally, the system was successfully

Observational infant exploratory [14C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis

PubMed Central

Garner, Colin R; Park, Kevin B; French, Neil S; Earnshaw, Caroline; Schipani, Alessandro; Selby, Andrew M; Byrne, Lindsay; Siner, Sarah; Crawley, Francis P; Vaes, Wouter H J; van Duijn, Esther; deLigt, Rianne; Varendi, Heili; Lass, Jane; Grynkiewicz, Grzegorz; Maruszak, Wioletta; Turner, Mark A

2015-01-01

Aims The aims of the study were to compare [14C]-paracetamol ([14C]-PARA) paediatric pharmacokinetics (PK) after administration mixed in a therapeutic dose or an isolated microdose and to develop further and validate accelerator mass spectrometry (AMS) bioanalysis in the 0–2 year old age group. Methods [14C]-PARA concentrations in 10–15 µl plasma samples were measured after enteral or i.v. administration of a single [14C]-PARA microdose or mixed in with therapeutic dose in infants receiving PARA as part of their therapeutic regimen. Results Thirty-four infants were included in the PARA PK analysis for this study: oral microdose (n = 4), i.v. microdose (n = 6), oral therapeutic (n = 6) and i.v. therapeutic (n = 18). The respective mean clearance (CL) values (SDs in parentheses) for these dosed groups were 1.46 (1.00) l h–1, 1.76 (1.07) l h–1, 2.93 (2.08) l h–1 and 2.72 (3.10) l h–1, t1/2 values 2.65 h, 2.55 h, 8.36 h and 7.16 h and dose normalized AUC(0-t) (mg l–1 h) values were 0.90 (0.43), 0.84 (0.57), 0.7 (0.79) and 0.54 (0.26). Conclusions All necessary ethical, scientific, clinical and regulatory procedures were put in place to conduct PK studies using enteral and systemic microdosing in two European centres. The pharmacokinetics of a therapeutic dose (mg kg–1) and a microdose (ng kg–1) in babies between 35 to 127 weeks post-menstrual age. [14C]-PARA pharmacokinetic parameters were within a two-fold range after a therapeutic dose or a microdose. Exploratory studies using doses significantly less than therapeutic doses may offer ethical and safety advantages with increased bionalytical sensitivity in selected exploratory paediatric pharmacokinetic studies. PMID:25619398

Observational infant exploratory [(14)C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis.

PubMed

Garner, Colin R; Park, Kevin B; French, Neil S; Earnshaw, Caroline; Schipani, Alessandro; Selby, Andrew M; Byrne, Lindsay; Siner, Sarah; Crawley, Francis P; Vaes, Wouter H J; van Duijn, Esther; deLigt, Rianne; Varendi, Heili; Lass, Jane; Grynkiewicz, Grzegorz; Maruszak, Wioletta; Turner, Mark A

2015-07-01

The aims of the study were to compare [(14)C]-paracetamol ([(14)C]-PARA) paediatric pharmacokinetics (PK) after administration mixed in a therapeutic dose or an isolated microdose and to develop further and validate accelerator mass spectrometry (AMS) bioanalysis in the 0-2 year old age group. [(14)C]-PARA concentrations in 10-15 µl plasma samples were measured after enteral or i.v. administration of a single [(14)C]-PARA microdose or mixed in with therapeutic dose in infants receiving PARA as part of their therapeutic regimen. Thirty-four infants were included in the PARA PK analysis for this study: oral microdose (n = 4), i.v. microdose (n = 6), oral therapeutic (n = 6) and i.v. therapeutic (n = 18). The respective mean clearance (CL) values (SDs in parentheses) for these dosed groups were 1.46 (1.00) l h(-1), 1.76 (1.07) l h(-1), 2.93 (2.08) l h(-1) and 2.72 (3.10) l h(-1), t(1/2) values 2.65 h, 2.55 h, 8.36 h and 7.16 h and dose normalized AUC(0-t) (mg l(-1) h) values were 0.90 (0.43), 0.84 (0.57), 0.7 (0.79) and 0.54 (0.26). All necessary ethical, scientific, clinical and regulatory procedures were put in place to conduct PK studies using enteral and systemic microdosing in two European centres. The pharmacokinetics of a therapeutic dose (mg kg(-1)) and a microdose (ng kg(-1)) in babies between 35 to 127 weeks post-menstrual age. [(14)C]-PARA pharmacokinetic parameters were within a two-fold range after a therapeutic dose or a microdose. Exploratory studies using doses significantly less than therapeutic doses may offer ethical and safety advantages with increased bionalytical sensitivity in selected exploratory paediatric pharmacokinetic studies. © 2015 The British Pharmacological Society.

A food effect study and dose proportionality study to assess the pharmacokinetics and safety of bardoxolone methyl in healthy volunteers.

PubMed

Teuscher, Nathan S; Kelley, Richard J; Dumas, Emily O; Klein, Cheri Enders; Awni, Walid M; Meyer, Colin J

2014-07-01

This study investigated the effect of food on the plasma pharmacokinetics of bardoxolone methyl, an antioxidant inflammation modulator, at a 20 mg dose, and the dose proportionality of bardoxolone methyl pharmacokinetics from 20 to 80 mg. It was a single-dose study conducted at a single center in 32 healthy volunteers aged 18-45 years using an amorphous spray-dried dispersion formulation of bardoxolone methyl. In Part A, 16 subjects received single 20 mg doses of bardoxolone methyl under fasting and non-fasting conditions. In Part B, 16 subjects received a single 60 or 80 mg dose of bardoxolone methyl and a matching placebo dose under fasting conditions. Blood samples for pharmacokinetic analysis were taken over 120 hours following dose administration. Single dose administration of 20, 60, and 80 mg bardoxolone methyl was safe and well-tolerated in healthy volunteers. Total bardoxolone methyl exposure was unchanged in the presence of food. However, doses of bardoxolone methyl above 20 mg appear to have a saturated dissolution or absorption process and are associated with less than proportional increases in drug exposure. © 2013, The American College of Clinical Pharmacology.

Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis.

PubMed

Winzenborg, Insa; Nader, Ahmed; Polepally, Akshanth R; Liu, Mohan; Degner, Jacob; Klein, Cheri E; Mostafa, Nael M; Noertersheuser, Peter; Ng, Juki

2018-02-23

Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters. The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis. Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F. Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.

[Role of food interaction pharmacokinetic studies in drug development. Food interaction studies of theophylline and nifedipine retard and buspirone tablets].

PubMed

Drabant, S; Klebovich, I; Gachályi, B; Renczes, G; Farsang, C

1998-09-01

Due to several mechanism, meals may modify the pharmacokinetics of drug products, thereby eliciting to clinically significant food interaction. Food interactions with the drug substance and with the drug formulation should be distinguished. Food interaction of different drug products containing the same active ingredient can be various depending on the pharmaceutical formulation technology. Particularly, in the case of modified release products, the food/formulation interaction can play an important role in the development of food interaction. Well known example, that bioavailability of theophylline can be influenced in different way (either increased, decreased or unchanged) by concomitant intake of food in the case of different sustained release products. The role and methods of food interaction studies in the different kinds of drug development (new chemical entity, modified release products, generics) are reviewed. Prediction of food effect response on the basis of the physicochemical and pharmacokinetic characteristics of the drug molecule or formulations is discussed. The results of three food interaction studies carried out the products of EGIS Pharmaceuticals Ltd. are also reviewed. The pharmacokinetic parameters of theophyllin 400 mg retard tablet were practically the same in both fasting condition and administration after consumption of a high fat containing standard breakfast. The ingestion of a high fat containing breakfast, increased the AUC of nifedipine from 259.0 +/- 101.2 ng h/ml to 326.7 +/- 122.5 ng h/ml and Cmax from 34.5 +/- 15.9 ng/ml to 74.3 +/- 23.9 ng/ml in case of nifedipine 20 mg retard tablet, in agreement with the data of literature. The statistical evaluation indicated significant differences between the pharmacokinetic parameters in the case of two administrations (before and after meal). The effect of a high fat containing breakfast for a generic version of buspiron 10 mg tablet and the bioequivalence after food consumption were

Does Critical Illness Change Levofloxacin Pharmacokinetics?

PubMed

Roberts, Jason A; Cotta, Menino Osbert; Cojutti, Piergiorgio; Lugano, Manuela; Della Rocca, Giorgio; Pea, Federico

2015-12-14

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Does Critical Illness Change Levofloxacin Pharmacokinetics?

PubMed Central

Cotta, Menino Osbert; Cojutti, Piergiorgio; Lugano, Manuela; Rocca, Giorgio Della; Pea, Federico

2015-01-01

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function. PMID:26666946

Pharmacokinetics of theophylline: a dose-range study.

PubMed Central

Rovei, V; Chanoine, F; Strolin Benedetti, M

1982-01-01

1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine-free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel). 2 Absorption of theophylline was rapid and followed first-order kinetics. Plasma curves were fitted according to a one compartment open model. 3 There was a linear relationship (P less than 0.001) between plasma Cmax or AUCx values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t1/2 abs, tmax, t1/2 beta, CL, CLR, Vd and F) were not modified at any dose. 4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3-dimethyluric acid (35 to 42%), 1-methyluric acid (21.3 to 26.7%) and 3-methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3-methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first-order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg). PMID:7150456

UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

EPA Science Inventory

Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment.

PubMed

Hira, Daiki; Chisaki, Yugo; Noda, Satoshi; Araki, Hisazumi; Uzu, Takashi; Maegawa, Hiroshi; Yano, Yoshitaka; Morita, Shin-Ya; Terada, Tomohiro

2015-01-01

The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m(2), including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment. © 2015 S. Karger AG, Basel.

Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies.

PubMed

Fu, Qiang; Sun, Jin; Zhang, Dong; Li, Mo; Wang, Yongjun; Ling, Guixia; Liu, Xiaohong; Sun, Yinghua; Sui, Xiaofan; Luo, Cong; Sun, Le; Han, Xiaopeng; Lian, He; Zhu, Meng; Wang, Siling; He, Zhonggui

2013-09-01

This study intended to develop nimodipine (NMD) nanocrystals with different sizes for oral administration and to investigate the relationship between dissolution and pharmacokinetics for NMD nanocrystals and Nimotop(®). NMD nanocrystals were prepared by combination of microprecipitation and high pressure homogenization and were further lyophilized. The particle size, morphology and aqueous solubility of the NMD nanocrystals were determined. With Nimotop(®) as the control, the dissolution rate was evaluated and the pharmacokinetic study was undertaken in beagle dogs. NMD nanocrystals with mean diameters of about 159.0, 503.0 and 833.3 nm were prepared, respectively. The lyophilization didn't affect the particle sizes of the redispersed nanocrystals. The aqueous solubility was significantly improved and displayed a size-dependent manner. The nanocrystals exhibited lower dissolution patterns than Nimotop(®) under non-sink condition, but bioavailability of the two nanocrystals (159.0 and 833.3 nm) was equivalent, about 2.6-fold higher than Nimotop(®). In conclusion, oral nanocrystal drug delivery system was a promising strategy in improving the oral bioavailability of poorly soluble or insoluble drugs. But we could not establish a favorable in vitro in vivo correlation for NMD nanocrystals and Nimotop(®) and thus the oral absorption mechanism of the NMD nanocrystals required further study. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation of the pre-posterior distribution of optimized sampling times for the design of pharmacokinetic studies.

PubMed

Duffull, Stephen B; Graham, Gordon; Mengersen, Kerrie; Eccleston, John

2012-01-01

Information theoretic methods are often used to design studies that aim to learn about pharmacokinetic and linked pharmacokinetic-pharmacodynamic systems. These design techniques, such as D-optimality, provide the optimum experimental conditions. The performance of the optimum design will depend on the ability of the investigator to comply with the proposed study conditions. However, in clinical settings it is not possible to comply exactly with the optimum design and hence some degree of unplanned suboptimality occurs due to error in the execution of the study. In addition, due to the nonlinear relationship of the parameters of these models to the data, the designs are also locally dependent on an arbitrary choice of a nominal set of parameter values. A design that is robust to both study conditions and uncertainty in the nominal set of parameter values is likely to be of use clinically. We propose an adaptive design strategy to account for both execution error and uncertainty in the parameter values. In this study we investigate designs for a one-compartment first-order pharmacokinetic model. We do this in a Bayesian framework using Markov-chain Monte Carlo (MCMC) methods. We consider log-normal prior distributions on the parameters and investigate several prior distributions on the sampling times. An adaptive design was used to find the sampling window for the current sampling time conditional on the actual times of all previous samples.

[Pharmacokinetic and clinical studies of flomoxef in the perinatal period].

PubMed

Matsuda, S; Hirayama, H; Oh, K; Tamate, K; Sengoku, K; Ishikawa, M; Shimizu, T; Haga, H; Hasegawa, T; Takada, H

1993-07-01

Pharmacokinetic and clinical studies on flomoxef (FMOX) in the perinatal period were carried out and following results were obtained 1. The pharmacokinetic parameter T1/2's of FMOX in maternal serum, umbilical cord serum and amniotic fluid in mothers after single intravenous injection of 1 g (n = 46) and 2 g (n = 34) were 1.11, 9.24, 9.24 hours and 2.54, 12.49, 12.49 hours, respectively. Cmax's and Tmax's of umbilical cord serum and amniotic fluid were 12.71, 11.77 micrograms/ml and 0.57, 3.35 hours upon single dose of 1 g i.v., and 35.17, 12.37 micrograms/ml and 0.32, 3.42 hours upon single dose of 2 g i.v., respectively. 2. Clinical usefulness were evaluated in 93 cases including were various infections in pregnancy and puerperal period. In pregnancy cases, clinical efficacy rate was 95.5% (21/22), and 100% in puerperal period. Bacteriological response rate was 84.6% (eradicated: 29, decreased: 4, unchanged: 2, replaced: 4 and unknown: 8 cases). No severe side effects nor clinical laboratory test results were observed in any cases. From above basic and clinical results, we conclude that FMOX is a useful and safe agent for various infections in pregnancy and puerperal period.

Pharmacokinetics of drugs in pregnancy.

PubMed

Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

2015-11-01

Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications. Copyright © 2015 Elsevier Inc. All rights reserved.

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

PubMed

McKeand, William

2017-09-01

Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation

Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

PubMed

Marsot, Amélie; Brevaut-Malaty, Véronique; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas

2014-08-01

Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

Microdialysis pharmacokinetic study of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration.

PubMed

Wei, Yan; Ying, Mingzhen; Xu, Shuai; Wang, Feng; Zou, Aifeng; Cao, Shilei; Jiang, Xinguo; Wang, Yajie

2016-01-01

The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. Tmax plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8-70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery.

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

PubMed

Cheng, Hao; Xie, Zhiliang; Jones, William P; Wei, Xiaohui Tracey; Liu, Zhongfa; Wang, Dasheng; Kulp, Samuel K; Wang, Jiang; Coss, Christopher C; Chen, Ching-Shih; Marcucci, Guido; Garzon, Ramiro; Covey, Joseph M; Phelps, Mitch A; Chan, Kenneth K

2016-05-01

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

Research Staff and Public Engagement: A UK Study

ERIC Educational Resources Information Center

Davies, Sarah R.

2013-01-01

Public engagement plays an important role in the contemporary UK academy, and is promoted through initiatives such as Beacons of Public Engagement and research grant "Pathways to Impact". Relatively little is known, however, about academic experiences of such engagement activities. This study focuses on one staff group, contract…

Raltegravir Pharmacokinetics in Patients on Asunaprevir-Daclatasvir

PubMed Central

Vincent, Corine; Furlan, Valérie; Rosa, Isabelle; Rosenthal, Eric; Cheret, Antoine; Molina, Jean-Michel; Taburet, Anne-Marie; Piroth, Lionel

2015-01-01

Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon–ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir. PMID:26438504

Analytical Techniques and Pharmacokinetics of Gastrodia elata Blume and Its Constituents.

PubMed

Wu, Jinyi; Wu, Bingchu; Tang, Chunlan; Zhao, Jinshun

2017-07-08

Gastrodia elata Blume ( G. elata ), commonly called Tianma in Chinese, is an important and notable traditional Chinese medicine (TCM), which has been used in China as an anticonvulsant, analgesic, sedative, anti-asthma, anti-immune drug since ancient times. The aim of this review is to provide an overview of the abundant efforts of scientists in developing analytical techniques and performing pharmacokinetic studies of G. elata and its constituents, including sample pretreatment methods, analytical techniques, absorption, distribution, metabolism, excretion (ADME) and influence factors to its pharmacokinetics. Based on the reported pharmacokinetic property data of G. elata and its constituents, it is hoped that more studies will focus on the development of rapid and sensitive analytical techniques, discovering new therapeutic uses and understanding the specific in vivo mechanisms of action of G. elata and its constituents from the pharmacokinetic viewpoint in the near future. The present review discusses analytical techniques and pharmacokinetics of G. elata and its constituents reported from 1985 onwards.

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

PubMed

Brown, Jacob T; Bishop, Jeffrey R

2015-01-01

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

A D-Optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients

PubMed Central

Hennig, Stefanie; Waterhouse, Timothy H; Bell, Scott C; France, Megan; Wainwright, Claire E; Miller, Hugh; Charles, Bruce G; Duffull, Stephen B

2007-01-01

What is already known about this subject • Itraconazole is a triazole antifungal used in the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis (CF). • The pharmacokinetic (PK) properties of this drug and its active metabolite have been described before, mostly in healthy volunteers. • However, only sparse information from case reports were available of the PK properties of this drug in CF patients at the start of our study. What this study adds • This study reports for the first time the population pharmacokinetic properties of itraconazole and a known active metabolite, hydroxy-itraconazole in adult patients with CF. • As a result, this study offers new dosing approaches and their pharmacoeconomic impact as well as a PK model for therapeutic drug monitoring of this drug in this patient group. • Furthermore, it is an example of a successful d-optimal design application in a clinical setting. Aim The primary objective of the study was to estimate the population pharmacokinetic parameters for itraconazole and hydroxy-itraconazole, in particular, the relative oral bioavailability of the capsule compared with solution in adult cystic fibrosis patients, in order to develop new dosing guidelines. A secondary objective was to evaluate the performance of a population optimal design. Methods The blood sampling times for the population study were optimized previously using POPT v.2.0. The design was based on the administration of solution and capsules to 30 patients in a cross-over study. Prior information suggested that itraconazole is generally well described by a two-compartment disposition model with either linear or saturable elimination. The pharmacokinetics of itraconazole and the metabolite were modelled simultaneously using NONMEM. Dosing schedules were simulated to assess their ability to achieve a trough target concentration of 0.5 mg ml−1. Results Out of 241 blood samples, 94% were taken within the defined optimal

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

Individual and population pharmacokinetic compartment analysis: a graphic procedure for quantification of predictive performance.

PubMed

Eksborg, Staffan

2013-01-01

Pharmacokinetic studies are important for optimizing of drug dosing, but requires proper validation of the used pharmacokinetic procedures. However, simple and reliable statistical methods suitable for evaluation of the predictive performance of pharmacokinetic analysis are essentially lacking. The aim of the present study was to construct and evaluate a graphic procedure for quantification of predictive performance of individual and population pharmacokinetic compartment analysis. Original data from previously published pharmacokinetic compartment analyses after intravenous, oral, and epidural administration, and digitized data, obtained from published scatter plots of observed vs predicted drug concentrations from population pharmacokinetic studies using the NPEM algorithm and NONMEM computer program and Bayesian forecasting procedures, were used for estimating the predictive performance according to the proposed graphical method and by the method of Sheiner and Beal. The graphical plot proposed in the present paper proved to be a useful tool for evaluation of predictive performance of both individual and population compartment pharmacokinetic analysis. The proposed method is simple to use and gives valuable information concerning time- and concentration-dependent inaccuracies that might occur in individual and population pharmacokinetic compartment analysis. Predictive performance can be quantified by the fraction of concentration ratios within arbitrarily specified ranges, e.g. within the range 0.8-1.2.

Population Pharmacokinetic Model for Cancer Chemoprevention With Sulindac in Healthy Subjects

PubMed Central

Berg, Alexander K.; Mandrekar, Sumithra J.; Ziegler, Katie L. Allen; Carlson, Elsa C.; Szabo, Eva; Ames, Mathew M.; Boring, Daniel; Limburg, Paul J.; Reid, Joel M.

2014-01-01

Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent. PMID:23436338

Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

PubMed

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

2017-11-15

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

[Pharmacokinetics of controlled-release oxycodone in patients with cancer pain].

PubMed

Nakamura, Kazuyo; Kokubun, Hideya; Komatsu, Toshiaki; Matoba, Motohiro; Hoka, Sumio; Yago, Kazuo

2007-09-01

Oxycodone is a useful analgesic for cancer patients in pain. However, its pharmacokinetics have not been sufficiently examined and there is a lack of information, with very few reports on pharmacokinetics concerning the absorption process in particular. With this in mind, we studied the pharmacokinetics of controlled-release oxycodone (Oxy contin). We measured its serum concentration in patients with cancer pain, and calculated parameters derived using the nonlinear least-squared method program (MULTI). In the result, pharmacokinetic parameters calculated at CL/F were: 45.6+/-22.0 L/hr (Mean+/-SD), Vd/F: 473.0+/-19 6.7 L, t(1/2): 7.2+/- 6.2 hr, kel: 0.103+/-0.034, kal: 1.082+/-0.604, Lag time: 0.9 9+/-0.40 hr. In addition, the serum oxycodone concentration hardly rose until 1 hour after and just before medication, whereupon a rapid increase was evident after 1 hour. The pharmacokinetics of controlled-release oxycodone in patients with cancer pain were clarified in this study. Especially during the absorption process, the lag time was calculated specifically at about 1 hour, making it approximately equal to MS contin.

Overseas trained nurses' perception of UK nurses' caring attitudes: a qualitative study.

PubMed

Alexis, Obrey

2009-08-01

The aim of this study was to explore overseas nurses' perception of their nursing colleagues' caring attitudes in the National Health Service (NHS) in the UK. A qualitative phenomenological approach using semi-structured interviews was used to obtain data from 12 overseas nurses. The interview transcripts were transcribed verbatim and analysed using van Manen thematic approach. Although many themes emerged following thematic analysis, this study will report the findings of three themes such as empathy, understanding and caring perspectives, emotional impact and lack of teamwork. In conclusion, this study provides an insight and it increases our understanding of overseas nurses' perceptions of their nursing colleagues' caring attitudes in the NHS in the UK. This paper concludes by indicating that teamwork, being empathetic, understanding and reducing emotional labour for overseas nurses could lead to a more satisfied working environment for overseas nurses in the NHS in the UK.

Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

PubMed

Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

2016-03-01

Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer.

PubMed

Yong, Wei Peng; Desai, Apurva A; Innocenti, Federico; Ramirez, Jacqueline; Shepard, Dale; Kobayashi, Ken; House, Larry; Fleming, Gini F; Vogelzang, Nicholas J; Schilsky, Richard L; Ratain, Mark J

2007-11-01

Etoposide is a widely used cytotoxic drug that is commercially available in both intravenous and oral formulations. High interpatient pharmacokinetic variability has been associated with oral etoposide administration. Various strategies used in the past to reduce such variability have not been successful. Hence, this study was designed to evaluate if pharmacokinetic modulation of oral etoposide with ketoconazole could lead to a favorable alteration of etoposide pharmacokinetics, and to assess the feasibility and safety of this approach. Thirty-two patients were treated with ketoconazole 200 mg daily with an escalating dose of oral etoposide starting at a dose of 50 mg every other day. Pharmacokinetic samples were obtained during the first treatment cycle after the administration of an oral etoposide and ketoconazole dose. Additional baseline pharmacokinetic studies of etoposide alone were performed 4 days prior to the first treatment cycle. Dose limiting toxicities were neutropenia and fatigue. Ketoconazole increased the area under the plasma concentration-time curve (AUC) of oral etoposide by a median of 20% (p < 0.005). Ketoconazole did not reduce the interpatient variability in etoposide pharmacokinetics. Pretreatment bilirubin levels correlated with etoposide clearance (Spearman's r = -0.48, p = 0.008). The maximum tolerated dose was etoposide administered at 50 mg daily and ketoconazole 200 mg qd for 3 of 5 weeks. Ketoconazole reduces the apparent clearance of oral etoposide, does not alter its toxicity profile and does not reduce interpatient pharmacokinetic variability. Other methods to reduce the pharmacokinetic variability of oral etoposide are needed.

Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity.

PubMed

Hahn, Roberta Zilles; Antunes, Marina Venzon; Verza, Simone Gasparin; Perassolo, Magda Susana; Suyenaga, Edna Sayuri; Schwartsmann, Gilberto; Linden, Rafael

2018-06-22

Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization. Copyright

Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect.

PubMed

Bocci, Guido; Kerbel, Robert S

2016-11-01

Metronomic chemotherapy describes the close, regular administration of chemotherapy drugs at less-toxic doses over prolonged periods of time. In 2015, the results of randomized phase III clinical trials demonstrated encouraging, albeit limited, efficacy benefits of metronomic chemotherapy regimens administered as adjuvant maintenance therapy for the treatment of breast cancer, or as maintenance therapy in combination with an antiangiogenic agent for metastatic colorectal cancer. Owing to the investigational nature of this approach, metronomic chemotherapy regimens are highly empirical in terms of the optimal dose and schedule for the drugs administered; therefore, greater knowledge of the pharmacokinetics of metronomic chemotherapy is critical to the future success of this treatment strategy. Unfortunately, such preclinical and clinical pharmacokinetic studies are rare. Herein, we present situations in which active drug concentrations have been achieved with metronomic schedules, and discuss their associated pharmacokinetic parameters. We summarize examples from the limited number of clinical studies in order to illustrate the importance of assessing such pharmacokinetic parameters, and discuss the influence this information can have on improving efficacy and reducing toxicity.

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs.

PubMed

Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kloft, Charlotte

2015-07-01

During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

Experimental asbestos studies in the UK: 1912-1950.

PubMed

Greenberg, Morris

2017-11-01

The asbestos industry originated in the UK in the 1870s. By 1898, asbestos had many applications and was reported to be one of the four leading causes of severe occupational disease. In 1912, the UK government sponsored an experimental study that reported that exposure to asbestos produced no more than a modicum of pulmonary fibrosis in guinea pigs. In the 1930s, the newly established Medical Research Council, with assistance from industry, sponsored a study of the effects of exposing animals to asbestos by injection (intratracheal and subcutaneous) and by inhalation in the factory environment. Government reports, publications, and contemporary records obtained by legal discovery have been reviewed in the context of the stage of scientific development and the history of the times. Experimenters were engaged in a learning process during the 1912-1950 period, and their reports of the effects of asbestos were inconsistent. Pathologists who studied the effects of asbestos experimentally, at whole animal, tissue and cellular levels, advanced experimental methodology and mechanistic knowledge. In the hands of public relations experts, however, research was exploited to preserve an industry and perpetuate preventable diseases, a practice that continues to this day. © 2017 Wiley Periodicals, Inc.

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

PubMed

Li, Jian; Chen, Rong; Yao, Qing-Yu; Liu, Sheng-Jun; Tian, Xiu-Yun; Hao, Chun-Yi; Lu, Wei; Zhou, Tian-Yan

2018-03-01

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E max equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E max equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

Multiple-Dose Pharmacokinetics of Fluvoxamine in Children and Adolescents.

ERIC Educational Resources Information Center

Labellarte, Michael; Biederman, Joseph; Emslie, Graham; Ferguson, James; Khan, Arifulla; Ruckle, Jon; Sallee, Randy; Riddle, Mark

2004-01-01

Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder…

[Simultaneous determination of daphnetin, daphnoretin, daphneticin in rat plasma by LC-MS/MS and its application in pharmacokinetic study].

PubMed

Hu, Yi-Yi-Li-Ge-Qi; Cao, Sa-Li; Lin, Long-Fei; Fu, Jing; Dong, Xiao-Xu; Yang, Chun-Jing; Zhang, Miao; Ni, Jian

2017-05-01

To establish HPLC-MS/MS method for simultaneous determination of daphnetin, daphnoretin, and daphneticin in rat plasma after oral and intravenous administration of Daphne giraldii extract, and then use them in the calculation of pharmacokinetic parameters. Six sprague-dawley rats received intragastric administration of D. giraldii extract (daphnetin, daphnoretin and daphneticin were 88.40, 3.24 and 4.28 mg•kg⁻¹, respectively). Their drug plasma concentration was determined by LC-MS/MS with schisandrin as an internal standard to draw plasma concentration-time curve. The pharmacokinetic parameters were calculated by Kinetica 4.4. The results showed that the linear range was 5-1 000 μg•L⁻¹ for daphnetin, daphnoretin and daphneticin, and the method ological test showed conformance to the requirements.The intraday and inter-day variable coefficients (RSD) were both less than 15.0%, indicating that both of legitimate precise and accuracy were consistent with the analysis requirements of biological samples. For daphnetin, the pharmacokinetic parameters Tmax, Cmax, AUC0-t, T1/2 and MRT were 4 h, 858.96 μg•L⁻¹, 10 566.4 μg•L⁻¹•h, 5.19 h and 9.43 h, respectively. For daphnoretin, the pharmacokinetic parameters Tmax, Cmax, AUC0-t, T1/2 and MRT were 2.92 h, 178.00 μg•L⁻¹, 905.89 μg•L⁻¹•h, 3.50 h and 6.95 h, respectively. For daphneticin, the pharmacokinetic parameters Tmax, Cmax, AUC0-t, T1/2 and MRT were 2 h, 36.67 μg•L⁻¹, 355.11 μg•L⁻¹•h, 4.95 h and 8.27 h, respectively. The LC-MS/MS analysis method established in this study was proved to be so accurate and sensitive that it can be applied to the pharmacokinetic study of daphnetin, daphnoretin and daphneticin. Copyright© by the Chinese Pharmaceutical Association.

Pharmacokinetics of Snake Venom

PubMed Central

Sanhajariya, Suchaya; Duffull, Stephen B.

2018-01-01

Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans. PMID:29414889

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers.

PubMed

Stifft, Frank; Vanmolkot, Floris; Scheffers, Ingrid; van Bortel, Luc; Neef, Cees; Christiaans, Maarten

2014-11-01

The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. © 2014 The British Pharmacological Society.

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

PubMed Central

Stifft, Frank; Vanmolkot, Floris; Scheffers, Ingrid; van Bortel, Luc; Neef, Cees; Christiaans, Maarten

2014-01-01

Aims The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Methods Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Results Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Conclusions Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. PMID:24809233

A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexole.

PubMed

Putri, Ratih S I; Setiawati, Effi; Aziswan, Syifa A; Ong, Fenny; Tjandrawinata, Raymond R; Susanto, Liana W

2016-11-18

The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of pramipexole evaluated in the study was manufactured by PT Dexa Medica, Palembang, Indonesia, the other, used as the reference, by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. All eligible subjects were required to fast before each drug administration period, which was separated by a one-week washout period. Pramipexole concentrations in plasma were assayed using a validated ultra performance liquid chromatography with mass spectrometry (UPLC-MS/MS) detector. The evaluated pharmacokinetic parameters included the area under the plasma concentration curve from time zero to the last observed measurable concentration (AUC 0-t ), the area under the plasma concentration curve extrapolated to infinite time (AUC 0-∞ ), the maximum plasma concentration (C max ), the time to reach C max (t max ), and the plasma concentration half-life (t 1/2 ). To evaluate the bioequivalence of those two pramipexole formulations, 90% confidence intervals (CIs) for geometric mean ratios of both formulations were calculated for AUC and C max parameters, while t max and t 1/2 differences were analyzed on the non-transformed data using Wilcoxon matched-pairs and a Student's paired t -test, respectively. The 90% CIs for the geometric mean ratios of the two pramipexole formulations were 95.89% (90.73%-101.34%), 95.53% (89.75%-101.68%), and 92.11% (84.35%-100.58%) for AUC 0-t , AUC 0-∞ , and C max , respectively. There were no statistically significant differences for t max and t 1/2 between the two pramipexole formulations. It is concluded that two pramipexole formulations in this study were bioequivalent.

A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexole

PubMed Central

Putri, Ratih S. I.; Setiawati, Effi; Aziswan, Syifa A.; Ong, Fenny; Tjandrawinata, Raymond R.; Susanto, Liana W.

2016-01-01

The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of pramipexole evaluated in the study was manufactured by PT Dexa Medica, Palembang, Indonesia, the other, used as the reference, by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. All eligible subjects were required to fast before each drug administration period, which was separated by a one-week washout period. Pramipexole concentrations in plasma were assayed using a validated ultra performance liquid chromatography with mass spectrometry (UPLC-MS/MS) detector. The evaluated pharmacokinetic parameters included the area under the plasma concentration curve from time zero to the last observed measurable concentration (AUC0-t), the area under the plasma concentration curve extrapolated to infinite time (AUC0-∞), the maximum plasma concentration (Cmax), the time to reach Cmax (tmax), and the plasma concentration half-life (t1/2). To evaluate the bioequivalence of those two pramipexole formulations, 90% confidence intervals (CIs) for geometric mean ratios of both formulations were calculated for AUC and Cmax parameters, while tmax and t1/2 differences were analyzed on the non-transformed data using Wilcoxon matched-pairs and a Student’s paired t-test, respectively. The 90% CIs for the geometric mean ratios of the two pramipexole formulations were 95.89% (90.73%–101.34%), 95.53% (89.75%–101.68%), and 92.11% (84.35%–100.58%) for AUC0-t, AUC0-∞, and Cmax, respectively. There were no statistically significant differences for tmax and t1/2 between the two pramipexole formulations. It is concluded that two pramipexole formulations in this study were bioequivalent. PMID:27869754

Pharmacokinetics and metabolism of radiolabelled SNI-2011, a novel muscarinic receptor agonist, in healthy volunteers. Comprehensive understanding of absorption, metabolism and excretion using radiolabelled SNI-2011.

PubMed

Washio, Takuo; Kohsaka, Kazuhiro; Arisawa, Hirohiko; Masunaga, Hiroaki; Nagatsuka, Shin-ichiro; Satoh, Yoshiaki

2003-01-01

The pharmacokinetics and metabolism of SNI-2011 ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the treatment of Sjögen's syndrome, were investigated in six healthy volunteers after a single oral administration of 14C-SNI-2011. After administration, plasma concentrations of the radioactivity and SNI-2011 reached to Cmax at approximately 2 h, and then decreased with t 1/2 of 9 and 4 h, respectively. Cmax and AUC0-infinity of the radioactivity in plasma were 2.2 and 5.0 times higher than those of SNI-2011, respectively. The main excretion route of the radioactivity was urine, and 97.3% of the dose excreted in urine within 168 h, indicating that 14C-SNI-2011 was completely absorbed. The mean recoveries of the metabolites in urine at 24 h after administration were 16.0% for SNI-2011, 35.8% for SNI-2011 trans-sulfoxide (SNI-t-SO), 8.7% for SNI-2011 cis-sulfoxide, 4.1% for SNI-2011 N-oxide, furthermore, two unknown metabolites, UK-1 and UK-2, were detected 14.6% and 7.7%, respectively. LC/MS analysis and hydrolysis studies revealed that UK-1 and UK-2 were glucuronic acid conjugates of SNI-2011 and SNI-t-SO, respectively.

[Pharmacokinetics of domestic actoprotector drug Metaprot in healthy volunteers].

PubMed

Kibal'chich, D A; Belolipetskaia, V G; Blagodatskikh, S V; Martsevich, S Iu; Rudenko, L I; Iatsuk, V R

2011-01-01

Pharmacokinetics of the actoprotector Metaprot, an original Russian drug, has been studied in a group of healthy adult volunteers. Metaprot in capsules was administrated orally as a single dose of 250 mg. The concentration of the active substance (ethylthiobenzimidazole) in the blood serum was determined by high-performance liquid chromatography (HPLC) with UV detection. The pharmacokinetic parameters were calculated by the model-independent method. The peak concentration of ethylthiobenzimidazole in plasma was Cmax = 0.91 +/- 1.05 microg/ml and the average time to peak concentration was t(max) = 1.06 +/- 0.16 h. A polymodal character of the distribution of pharmacokinetic parameters in the test group was revealed.

Pharmacokinetic study of aniracetam in elderly patients with cerebrovascular disease.

PubMed

Endo, H; Tajima, T; Yamada, H; Igata, A; Yamamoto, Y; Tsuchida, H; Nakashima, Y; Suzuki, Y; Ikari, H; Iguchi, A

1997-02-01

The clinical pharmacokinetics of the cognitive enhancer, aniracetam (200 mg), was studied in elderly patients with cerebrovascular disease (CVD) and compared with those of young healthy volunteers. Six female hospitalized patients (mean age 84.5 years) were used in this study. The serum level of anisic acid and p-methoxyhippuric acid, major metabolites of aniracetam, reached a peak at 2 h after oral administration, and returned to basal level by 6 h. Mean creatinine clearance was 20-30 ml/min. The t1/2 of metabolites was increased by 4- to 7-fold in the elderly patients compared with young volunteers. This study showed that tmax, t1/2, and AUC were enlarged in the elderly; however, no clinical side effects were observed.

A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients

PubMed Central

Zandvliet, Maarten L.; Koolen, Stijn L. W.; Mathijssen, Ron H. J.; van der Rijt, Carin C. D.

2016-01-01

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer‐related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter‐ and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side‐effects and increasing its efficacy. PMID:27619152

Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

PubMed Central

Minassian, S. L.; Morris, D.; Ponnuraj, R.; Marbury, T. C.; Alcorn, H. W.; Fang, E.; Prokocimer, P.

2014-01-01

Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study

Centralization of cleft care in the UK. Part 6: a tale of two studies

PubMed Central

Ness, A R; Wills, A K; Waylen, A; Al-Ghatam, R; Jones, T E M; Preston, R; Ireland, A J; Persson, M; Smallridge, J; Hall, A J; Sell, D; Sandy, J R

2015-01-01

Structured Abstract Objectives We summarize and critique the methodology and outcomes from a substantial study which has investigated the impact of reconfigured cleft care in the United Kingdom (UK) 15 years after the UK government started to implement the centralization of cleft care in response to an earlier survey in 1998, the Clinical Standards Advisory Group (CSAG). Setting and Sample Population A UK multicentre cross-sectional study of 5-year-olds born with non-syndromic unilateral cleft lip and palate. Data were collected from children born in the UK with a unilateral cleft lip and palate between 1 April 2005 and 31 March 2007. Materials and Methods We discuss and contextualize the outcomes from speech recordings, hearing, photographs, models, oral health and psychosocial factors in the current study. We refer to the earlier survey and other relevant studies. Results We present arguments for centralization of cleft care in healthcare systems, and we evidence this with improvements seen over a period of 15 years in the UK. We also make recommendations on how future audit and research may configure. Conclusions Outcomes for children with a unilateral cleft lip and palate have improved after the introduction of a centralized multidisciplinary service, and other countries may benefit from this model. Predictors of early outcomes are still needed, and repeated cross-sectional studies, larger longitudinal studies and adequately powered trials are required to create a research-led evidence-based (centralized) service. PMID:26567856

Pharmacokinetics, Metabolism, Distribution and Permeability of Nanomedicine.

PubMed

Ravindran, Selvan; Suthar, Jitendra Kumar; Rokade, Rutuja; Deshpande, Pooja; Singh, Pooja; Pratinidhi, Ashutosh; Khambadkhar, Rajeshree; Utekar, Srushti

2018-01-01

Medical application of nanotechnology is termed as Nanomedicine and is widely used in healthcare industries. Nanotechnology has helped Physicians, Scientists and Technologists to understand the changes in cellular levels to develop nanomedicines and address the challenges faced by the healthcare sectors. Nanoparticles with less than 1nm in size have been used as drug delivery and gene delivery systems to accelerate the drug action in humans. Size of nanomaterials is akin to that of biomolecules and expected to have better interactions. Hence, its utility for various biomedical applications is explored. Pharmacokinetics, metabolism, permeability, distribution and elimination studies of nanoparticles are essential to understand its potency, toxicity threshold and confirm its safe use in humans. Reports were available for toxicity studies on nanoparticles, but work on metabolism, pharmacokinetics, distribution and permeability of nanomedicine is limited. Hence, the main focus of this review article is about metabolism, pharmacokinetics, permeability and biodistribution of nanomaterials used in nanomedicine. Nanomedicine is increasingly becoming important in the treatment of diseases and diagnosis. Size of the particle plays an important role. As the particle size decreases its effect to cure the disease increases. Pharmacokinetics, bioavailability, half-life, metabolism, biodistribution and permeability of nanomedicine were found to be better than that of microsized drugs. In vitro and In vivo ADME (Absorption, Distribution, Metabolism and Excretion) studies are mandatory for pharmaceutical organic drugs. Similarly, nanomaterials should be subjected to both in vitro and in vivo ADME studies. Thus, nanomedicine can assist in the development of safe personalized medicine in humans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Descriptive Study of Professional Staff, and Their Careers, in Australian and UK Universities

ERIC Educational Resources Information Center

Gander, Michelle

2018-01-01

Professional staff total approximately 23% of staff in universities in the UK, which in 2014/15 was the equivalent of 95,870 individuals (hesa.ac.uk). With their increasing span of responsibility, it is surprising that there has been little research into the careers of these staff. This study, part of a larger careers study, highlights some key…

A pilot study on the serum pharmacokinetics of nattokinase in humans following a single, oral, daily dose.

PubMed

Ero, Michael Penfield; Ng, Connie M; Mihailovski, Tamara; Harvey, Nathaniel R; Lewis, Brad Howard

2013-01-01

Nattokinase is a serine protease and is derived from natto, a traditional Japanese, fermented, soybean food meal. Multiple authors have described the significant fibrinolytic, antithrombotic, and antihypertensive effects of natto. Nattokinase has been growing in popularity for use as a dietary supplement for the benefit of cardiovascular health. Little is known regarding the pharmacokinetic and pharmacodynamic properties of this enzyme, and the bioavailability of nattokinase is currently unknown. This study intended to (1) detect nattokinase directly and immunologically, (2) show that nattokinase and/or its metabolites were detectable in human blood following ingestion of a commercial preparation, and (3) chart a pharmacokinetic dosing effect for nattokinase. The research team designed the pilot study as an in vivo, human clinical trial. Healthy human subjects responded to an advertisement and were screened. Subjects who satisfied both inclusion and exclusion criteria were enrolled into the study. Subjects were then instructed to orally ingest a single capsule containing a known concentration of nattokinase immediately following a baseline blood draw. Subsequent blood draws occurred over a 24-h period. This study was conducted in Oakland, California, at a clinical reference laboratory and was performed with the approval of an institutional review board (IRB) to ensure that appropriate ethical standards were met. Eleven healthy participants (five male, six female, ages 21-65), who met eligibility criteria, were enrolled. Administration of nattokinase occurred orally with the ingestion of a single daily dose (2000 FU) of nattokinase. Capsules, each containing approximately 100 mg of nattokinase, in softgel form (NSK-SD, Japan Bio Science Laboratory, Osaka, Japan), were used in the study. Baseline blood samples were collected, and participants were observed swallowing a single capsule of the nattokinase supplement before returning at 2, 4, 8, 12, 24, and 48 h post

Anti-colchicine Fab fragments prevent lethal colchicine toxicity in a porcine model: a pharmacokinetic and clinical study.

PubMed

Eddleston, Michael; Fabresse, Nicolas; Thompson, Adrian; Al Abdulla, Ibrahim; Gregson, Rachael; King, Tim; Astier, Alain; Baud, Frederic J; Clutton, R Eddie; Alvarez, Jean-Claude

2018-08-01

Colchicine poisoning is commonly lethal. Colchicine-specific Fab fragments increase rat urinary colchicine clearance and have been associated with a good outcome in one patient. We aimed to develop a porcine model of colchicine toxicity to study the pharmacokinetics and efficacy of ovine Fab. A Göttingen minipig critical care model was established and serial blood samples taken for colchicine and Fab pharmacokinetics, clinical chemistry, and haematology. Animals were euthanised when the mean arterial pressure fell below 45 mmHg without response to vasopressor, or at study completion. Initial studies indicated that oral dosing produced variable pharmacokinetics and time-to-euthanasia. By contrast, intravenous infusion of 0.25 mg/kg colchicine over 1 h produced reproducible pharmacokinetics (AUC 0-20 343 [SD = 21] µg/L/h), acute multi-organ injury, and cardiotoxicity requiring euthanasia a mean of 22.5 (SD = 3.2) h after dosing. A full-neutralising equimolar Fab dose given 6 h after the infusion (50% first hour, 50% next 6 h [to reduce renal-loss of unbound Fab]) produced a 7.35-fold increase in plasma colchicine (AUC 0-20 2,522 [SD = 14] µg/L/h), and removed all free plasma colchicine, but did not prevent toxicity (euthanasia at 29.1 [SD = 3.4] h). Earlier administration over 1 h of the full-neutralising dose, 1 or 3 h after the colchicine, produced a 12.9-fold (AUC 0-20 4,433 [SD = 607] µg/L/h) and 6.0-fold (AUC 0-20 2,047 [SD = 51] µg/L/h) increase in plasma colchicine, respectively, absence of free plasma colchicine until 20 h, and survival to study end without marked cardiotoxicity. Colchicine-specific Fab given early, in equimolar dose, bound colchicine, eliciting its movement into the blood, and preventing severe toxicity. Clinical studies are now needed to determine how soon this antidote must be given to work in human poisoning.

Monocular and binocular visual impairment in the UK Biobank study: prevalence, associations and diagnoses.

PubMed

McKibbin, Martin; Farragher, Tracey M; Shickle, Darren

2018-01-01

To determine the prevalence of, associations with and diagnoses leading to mild visual impairment or worse (logMAR >0.3) in middle-aged adults in the UK Biobank study. Prevalence estimates for monocular and binocular visual impairment were determined for the UK Biobank participants with fundus photographs and spectral domain optical coherence tomography images. Associations with socioeconomic, biometric, lifestyle and medical variables were investigated for cases with visual impairment and matched controls, using multinomial logistic regression models. Self-reported eye history and image grading results were used to identify the primary diagnoses leading to visual impairment for a sample of 25% of cases. For the 65 033 UK Biobank participants, aged 40-69 years and with fundus images, 6682 (10.3%) and 1677 (2.6%) had mild visual impairment or worse in one or both eyes, respectively. Increasing deprivation, age and ethnicity were independently associated with both monocular and binocular visual impairment. No primary diagnosis for the recorded level of visual impairment could be identified for 49.8% of eyes. The most common identifiable diagnoses leading to visual impairment were cataract, amblyopia, uncorrected refractive error and vitreoretinal interface abnormalities. The prevalence of visual impairment in the UK Biobank study cohort is lower than for population-based studies from other industrialised countries. Monocular and binocular visual impairment are associated with increasing deprivation, age and ethnicity. The UK Biobank dataset does not allow confident identification of the causes of visual impairment, and the results may not be applicable to the wider UK population.

Monocular and binocular visual impairment in the UK Biobank study: prevalence, associations and diagnoses

PubMed Central

Farragher, Tracey M; Shickle, Darren

2018-01-01

Objective To determine the prevalence of, associations with and diagnoses leading to mild visual impairment or worse (logMAR >0.3) in middle-aged adults in the UK Biobank study. Methods and analysis Prevalence estimates for monocular and binocular visual impairment were determined for the UK Biobank participants with fundus photographs and spectral domain optical coherence tomography images. Associations with socioeconomic, biometric, lifestyle and medical variables were investigated for cases with visual impairment and matched controls, using multinomial logistic regression models. Self-reported eye history and image grading results were used to identify the primary diagnoses leading to visual impairment for a sample of 25% of cases. Results For the 65 033 UK Biobank participants, aged 40–69 years and with fundus images, 6682 (10.3%) and 1677 (2.6%) had mild visual impairment or worse in one or both eyes, respectively. Increasing deprivation, age and ethnicity were independently associated with both monocular and binocular visual impairment. No primary diagnosis for the recorded level of visual impairment could be identified for 49.8% of eyes. The most common identifiable diagnoses leading to visual impairment were cataract, amblyopia, uncorrected refractive error and vitreoretinal interface abnormalities. Conclusions The prevalence of visual impairment in the UK Biobank study cohort is lower than for population-based studies from other industrialised countries. Monocular and binocular visual impairment are associated with increasing deprivation, age and ethnicity. The UK Biobank dataset does not allow confident identification of the causes of visual impairment, and the results may not be applicable to the wider UK population. PMID:29657974

The Benefits of Part-Time Undergraduate Study and UK Higher Education Policy: A Literature Review

ERIC Educational Resources Information Center

Bennion, Alice; Scesa, Anna; Williams, Ruth

2011-01-01

Part-time study in the UK is significant: nearly 40 per cent of higher education students study part-time. This article reports on a literature review that sought to understand the economic and social benefits of part-time study in the UK. It concludes that there are substantial and wide-ranging benefits from studying part-time. The article also…

Pharmacokinetics of Rhodamine 110 and Its Organ Distribution in Rats.

PubMed

Jiang, Shiau-Han; Cheng, Yung-Yi; Huo, Teh-Ia; Tsai, Tung-Hu

2017-09-06

Rhodamine dyes have been banned as food additives due to their potential tumorigenicity. Rhodamine 110 is illegal as a food additive, although its pharmacokinetics have not been characterized, and no accurate bioanalytical methods are available to quantify rhodamine 110. The aim of this study was to develop and validate a fast, stable, and sensitive method to quantify rhodamine 110 using high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) to assess its pharmacokinetics and organ distribution in awake rats. Rhodamine 110 exhibited linear pharmacokinetics and slow elimination after oral administration. Furthermore, its oral bioavailability was approximately 34-35%. The distribution in the liver and kidney suggests that these organs are primarily responsible for rhodamine 110 metabolism and elimination. Our investigation describes the pharmacokinetics and a quantification method for rhodamine 110, improving our understanding of the food safety of rhodamine dyes.

Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

PubMed Central

Tréluyer, Jean-Marc; Illamola, Silvia M.; Bouazza, Naïm; Foissac, Frantz; De Sousa Mendes, Maïlys; Lui, Gabrielle; Chenevier-Gobeaux, Camille; Suzan-Monti, Marie; Rouzioux, Christine; Assoumou, Lambert; Viard, Jean-Paul; Hirt, Déborah; Urien, Saïk; Ghosn, Jade

2015-01-01

We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were higher in SP than in BP (median AUC0–24, 38.04 and 12.95 mg · liter−1 · h, respectively). The median (range) SP-to-BP AUC0–24 ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC0–24 ratios were lower than 1. The impact of FTC SP AUC0–24 or FTC SP-to-BP AUC0–24 ratio on spVL detection was not significant (P = 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men. PMID:26282407

The UK Biobank sample handling and storage validation studies.

PubMed

Peakman, Tim C; Elliott, Paul

2008-04-01

and aims UK Biobank is a large prospective study in the United Kingdom to investigate the role of genetic factors, environmental exposures and lifestyle in the causes of major diseases of late and middle age. It involves the collection of blood and urine from 500 000 individuals aged between 40 and 69 years. How the samples are collected, processed and stored will have a major impact on the future scientific usefulness of the UK Biobank resource. A series of validation studies was recommended to test the robustness of the draft sample handling and storage protocol. Samples of blood and urine were collected from 40 healthy volunteers and either processed immediately according to the protocol or maintained at specified temperatures (4 degrees C for all tubes with the exception of vacutainers containing acid citrate dextrose that were maintained at 18 degrees C) for 12, 24 or 36 h prior to processing. A further sample was maintained for 24 h at 4 degrees C, processed and the aliquots frozen at -80 degrees C for 20 days and then thawed under controlled conditions. The stability of the samples was compared for the different times in a wide variety of assays. The samples maintained at 4 degrees C were stable for at least 24 h after collection for a wide range of assays. Small but significant changes were observed in metabonomic studies in samples maintained at 4 degrees C for 36 h. There was no degradation of the samples for a range of biochemical assays after short-term freezing and thawing under controlled conditions. Whole blood maintained at 18 degrees C for 24 h in vacutainers containing acid citrate dextrose is suitable for viral immortalization techniques. The validation studies reported in this supplement provide justification for the sample handling and storage procedures adopted in the UK Biobank project.

Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects.

PubMed

Dolder, Patrick C; Schmid, Yasmin; Steuer, Andrea E; Kraemer, Thomas; Rentsch, Katharina M; Hammann, Felix; Liechti, Matthias E

2017-10-01

Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD. We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups. The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related

Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies (Final Report)

EPA Science Inventory

EPA announced the availability of the final report, Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies. This report summarizes some of the recent progress in characterizing uncertainty and variability in physi...

Checking distributional assumptions for pharmacokinetic summary statistics based on simulations with compartmental models.

PubMed

Shen, Meiyu; Russek-Cohen, Estelle; Slud, Eric V

2016-08-12

Bioequivalence (BE) studies are an essential part of the evaluation of generic drugs. The most common in vivo BE study design is the two-period two-treatment crossover design. AUC (area under the concentration-time curve) and Cmax (maximum concentration) are obtained from the observed concentration-time profiles for each subject from each treatment under each sequence. In the BE evaluation of pharmacokinetic crossover studies, the normality of the univariate response variable, e.g. log(AUC) 1 or log(Cmax), is often assumed in the literature without much evidence. Therefore, we investigate the distributional assumption of the normality of response variables, log(AUC) and log(Cmax), by simulating concentration-time profiles from two-stage pharmacokinetic models (commonly used in pharmacokinetic research) for a wide range of pharmacokinetic parameters and measurement error structures. Our simulations show that, under reasonable distributional assumptions on the pharmacokinetic parameters, log(AUC) has heavy tails and log(Cmax) is skewed. Sensitivity analyses are conducted to investigate how the distribution of the standardized log(AUC) (or the standardized log(Cmax)) for a large number of simulated subjects deviates from normality if distributions of errors in the pharmacokinetic model for plasma concentrations deviate from normality and if the plasma concentration can be described by different compartmental models.

[The role of bemitil pharmacokinetics in realizing its therapeutic efficacy].

PubMed

Boĭko, S S; Zherdev, V P; Neznamov, G G

1991-01-01

The pharmacokinetics of a new psychotropic drug bemithil was studied after single and long-term administrations under monotherapy and in combination with phenazepam in patients with asthenoneurotic disturbances. A high degree of correlation for some pharmacokinetic parameters of bemithil following the administration of the drug test dose and its global therapeutic effect was established.

Pharmacokinetics of isotretinoin during repetitive dosing to patients.

PubMed

Brazzell, R K; Vane, F M; Ehmann, C W; Colburn, W A

1983-01-01

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.

[Population pharmacokinetics applied to optimising cisplatin doses in cancer patients].

PubMed

Ramón-López, A; Escudero-Ortiz, V; Carbonell, V; Pérez-Ruixo, J J; Valenzuela, B

2012-01-01

To develop and internally validate a population pharmacokinetics model for cisplatin and assess its prediction capacity for personalising doses in cancer patients. Cisplatin plasma concentrations in forty-six cancer patients were used to determine the pharmacokinetic parameters of a two-compartment pharmacokinetic model implemented in NONMEN VI software. Pharmacokinetic parameter identification capacity was assessed using the parametric bootstrap method and the model was validated using the nonparametric bootstrap method and standardised visual and numerical predictive checks. The final model's prediction capacity was evaluated in terms of accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles. Mean population cisplatin clearance is 1.03 L/h with an interpatient variability of 78.0%. Estimated distribution volume at steady state was 48.3 L, with inter- and intrapatient variabilities of 31,3% and 11,7%, respectively. Internal validation confirmed that the population pharmacokinetics model is appropriate to describe changes over time in cisplatin plasma concentrations, as well as its variability in the study population. The accuracy and precision of a posteriori prediction of cisplatin concentrations improved by 21% and 54% compared to a priori prediction. The population pharmacokinetic model developed adequately described the changes in cisplatin plasma concentrations in cancer patients and can be used to optimise cisplatin dosing regimes accurately and precisely. Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.

Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data.

PubMed

Del Amo, Eva M; Urtti, Arto

2015-08-01

Intravitreal administration is the method of choice in drug delivery to the retina and/or choroid. Rabbit is the most commonly used animal species in intravitreal pharmacokinetics, but it has been criticized as being a poor model of human eye. The critique is based on some anatomical differences, properties of the vitreous humor, and observed differences in drug concentrations in the anterior chamber after intravitreal injections. We have systematically analyzed all published information on intravitreal pharmacokinetics in the rabbit and human eye. The analysis revealed major problems in the design of the pharmacokinetic studies. In this review we provide advice for study design. Overall, the pharmacokinetic parameters (clearance, volume of distribution, half-life) in the human and rabbit eye have good correlation and comparable absolute values. Therefore, reliable rabbit-to-man translation of intravitreal pharmacokinetics should be feasible. The relevant anatomical and physiological parameters in rabbit and man show only small differences. Furthermore, the claimed discrepancy between drug concentrations in the human and rabbit aqueous humor is not supported by the data analysis. Based on the available and properly conducted pharmacokinetic studies, the differences in the vitreous structure in rabbits and human patients do not lead to significant pharmacokinetic differences. This review is the first step towards inter-species translation of intravitreal pharmacokinetics. More information is still needed to dissect the roles of drug delivery systems, disease states, age and ocular manipulation on the intravitreal pharmacokinetics in rabbit and man. Anyway, the published data and the derived pharmacokinetic parameters indicate that the rabbit is a useful animal model in intravitreal pharmacokinetics. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

A pilot pharmacokinetic study of miroestrol and deoxymiroestrol on rabbit sera using polyclonal antibody-based icELISA analysis.

PubMed

Kitisripanya, Tharita; Udomsin, Orapin; Komaikul, Jukrapun; Inyai, Chadathorn; Limsuwanchote, Supattra; Yusakul, Gorawit; Putalun, Waraporn

2018-02-01

Miroestrol (ME) and deoxymiroestrol (DME) are the most potent phytoestrogens and bioactive markers in Pueraria candollei var. mirifica tuberous roots. To understand their pharmacokinetic profiles, a pharmacokinetic study of ME and DME, at 0.43 and 0.21 mg per kg body weight, respectively, in three rabbits was performed after orally administering a single dose of P. candollei var. mirifica enriched fraction extract. Two established polyclonal antibody-based indirect competitive enzyme-linked immunosorbent assays were validated to determine ME and DME in rabbit sera. In rabbits, the area under the 0- to 48-hr concentration-time curve of ME and DME were 854.92 and 1,692.84 ng·h/ml, respectively. The maximum concentration of ME was measured 1 hr after administration as 69.62 ± 8.28 ng/ml, and the maximum concentration of DME was measured at 3 hr as 81.8 ± 5.43 ng/ml. These results provide an initial approach for designing and studying the relationship between the ME and DME levels and their therapeutic effects based on their pharmacokinetic profiles. Copyright © 2017 John Wiley & Sons, Ltd.

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.

PubMed

Madelain, Vincent; Guedj, Jérémie; Mentré, France; Nguyen, Thi Huyen Tram; Jacquot, Frédéric; Oestereich, Lisa; Kadota, Takumi; Yamada, Koichi; Taburet, Anne-Marie; de Lamballerie, Xavier; Raoul, Hervé

2017-01-01

Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC 50 ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC 50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses. Copyright © 2016 American Society for Microbiology.

A general method to determine sampling windows for nonlinear mixed effects models with an application to population pharmacokinetic studies.

PubMed

Foo, Lee Kien; McGree, James; Duffull, Stephen

2012-01-01

Optimal design methods have been proposed to determine the best sampling times when sparse blood sampling is required in clinical pharmacokinetic studies. However, the optimal blood sampling time points may not be feasible in clinical practice. Sampling windows, a time interval for blood sample collection, have been proposed to provide flexibility in blood sampling times while preserving efficient parameter estimation. Because of the complexity of the population pharmacokinetic models, which are generally nonlinear mixed effects models, there is no analytical solution available to determine sampling windows. We propose a method for determination of sampling windows based on MCMC sampling techniques. The proposed method attains a stationary distribution rapidly and provides time-sensitive windows around the optimal design points. The proposed method is applicable to determine sampling windows for any nonlinear mixed effects model although our work focuses on an application to population pharmacokinetic models. Copyright © 2012 John Wiley & Sons, Ltd.

Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis.

PubMed

Aoyama, T; Hirata, K; Yamamoto, Y; Yokota, H; Hayashi, H; Aoyama, Y; Matsumoto, Y

2016-08-01

Midazolam (MDZ) is commonly used for sedating critically ill patients. The daily dose required for adequate sedation increases in increments over 100 h after administration. The objectives of this study were to characterize the MDZ pharmacokinetics in critically ill patients and to describe the phenomenon of increasing daily dose by means of population pharmacokinetic analysis. Data were obtained from 30 patients treated in an intensive care unit. The patients received MDZ intravenously as a combination of bolus and continuous infusion. Serum MDZ concentration was assayed by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using the NONMEM software package. The alteration of clearance unexplained by demographic factors and clinical laboratory data was described as an autoinduction of MDZ clearance using a semi-mechanistic pharmacokinetic-enzyme turnover model. The final population pharmacokinetic model was a one-compartment model estimated by incorporating a semi-mechanistic pharmacokinetic-enzyme turnover model for clearance, taking autoinduction into account. A significant covariate for MDZ clearance was total bilirubin. An increase in total bilirubin indicated a reduction in MDZ clearance. From simulation using the population pharmacokinetic parameters obtained in this study, MDZ clearance increased 2·3 times compared with pre-induced clearance 100 h after the start of 12·5 mg/h continuous infusion. Autoinduction and total bilirubin were significant predictors of the clearance of MDZ in this population. Step-by-step dosage adjustment using this population pharmacokinetic model may be useful for establishing a MDZ dosage regimen in critically ill patients. © 2016 John Wiley & Sons Ltd.

Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women.

PubMed

Blode, Hartmut; Kowal, Kristin; Roth, Katrin; Reif, Stefanie

2012-08-01

To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women. Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.02 mg/DRSP 3 mg over 21 consecutive days in Caucasian and Japanese women (Study 3). In Studies 1 and 2, there was a linear dose-dependent increase in DRSP C(max) and systemic exposure across the range of doses used in both ethnic groups. The co- administration of EE had no relevant effect on the pharmacokinetic parameters of 3 mg DRSP. In Study 3, steady-state DRSP concentrations were achieved after about eight days of treatment in both ethnic groups with approximately a threefold accumulation. There was about a twofold EE accumulation over 21 days in both ethnic groups. There were no differences in DRSP or EE exposure at day 21 between ethnic groups; the ratio of the geometric means (Japanese/Caucasian) of the AUC(0-24h) were 1.05 (90% CI: 0.95-1.17) and 1.02 (90% CI: 0.76-1.38), respectively. Ethnic origin had no clinically relevant influence on the pharmacokinetics of DRSP and EE.

Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women

PubMed Central

Blode, Hartmut; Kowal, Kristin; Roth, Katrin; Reif, Stefanie

2012-01-01

Objective To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women. Method Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.02 mg/DRSP 3 mg over 21 consecutive days in Caucasian and Japanese women (Study 3). Results In Studies 1 and 2, there was a linear dose-dependent increase in DRSP Cmax and systemic exposure across the range of doses used in both ethnic groups. The coadministration of EE had no relevant effect on the pharmacokinetic parameters of 3 mg DRSP. In Study 3, steady-state DRSP concentrations were achieved after about eight days of treatment in both ethnic groups with approximately a threefold accumulation.There was about a twofold EE accumulation over 21 days in both ethnic groups. There were no differences in DRSP or EE exposure at day 21 between ethnic groups; the ratio of the geometric means (Japanese/Caucasian) of the AUC0−24h were 1.05 (90% CI: 0.95–1.17) and 1.02 (90% CI: 0.76–1.38), respectively. Conclusion Ethnic origin had no clinically relevant influence on the pharmacokinetics of DRSP and EE. PMID:22680989

Pharmacokinetic modeling in aquatic animals. 1. Models and concepts

USGS Publications Warehouse

Barron, M.G.; Stehly, Guy R.; Hayton, W.L.

1990-01-01

While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetics modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination.

Report: pharmacokinetic and drug interaction studies of pefloxacin with paracetamol (NNAID) in healthy volunteers in Pakistan.

PubMed

Gauhar, Shahnaz; Ali, Syed Ayub; Naqvi, Syed Baqir; Shoaib, Muhammad Harris

2014-03-01

In the present study, the pharmacokinetic and drug interaction evaluation of two drugs pefloxacin and paracetamol was carried out by a single-dose, two-treatment and two-sequence crossover design. Total fifteen healthy volunteers participated out of which ten completed the study. All were male volunteers, aged 22.36 years (means), with a mean weight of 76.45±12.05 Kg. The washout period between treatments was 5 week. Initially the method utilized for quantitative analysis of the drug was developed which was further validated. The study involved plasma protein precipitation with ethyl acetate and detection was done at 275nm. The retention time for pefloxacin 18±1 min and paracetamol were approximately 6±1 min, respectively. The calibration curve for pefloxacin was linear in the concentration range of 0.125-12.0mg/ml with r(2)=0.9987 in plasma. Standard concentration solution was maintained on the same temperature as that of volunteer's samples to optimize the periods for the determination of drug concentration in the plasma samples. Blood samples were collected from volunteers at different time intervals. The pharmacokinetics and drug interaction studies were anticipated by plotting concentration versus time-profiles. The value of AUC0-∞ in control was 67.355±3.174μg.h/ml, in treatment 61.242±3.868μg.h/ml along with relative bioavailability =91.395±4.864. Under the control and treatment condition the mean maximum plasma concentrations were found to be 4.679±0.248 μg/ml and 4.6595±0.266 μg/ml respectively. The average T(max) for plasma concentrations was 1.819±0.1743hr and 1.605 ±0.1134hr respectively. The biological half-lives in the two phases of studies were found to be 7.953±0.33hr in control and 7.7257±0.355hr in treatment. No significant effect were observed on the bioavailability and pharmacokinetics of pefloxacin by the concomitant administration with paracetamol, however very minor effect were observed that might be related with inter

A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

PubMed

van Iersel, Marlou L P S; Rossenu, Stefaan; de Greef, Rik; Waskin, Hetty

2018-04-30

A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia vs allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (single dose vs multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/l) to a broad range of patients at high risk for invasive fungal disease. Copyright © 2018 American Society for Microbiology.

The use of gas chromatographic-mass spectrometric-computer systems in pharmacokinetic studies.

PubMed

Horning, M G; Nowlin, J; Stafford, M; Lertratanangkoon, K; Sommer, K R; Hill, R M; Stillwell, R N

1975-10-29

Pharmacokinetic studies involving plasma, urine, breast milk, saliva and liver homogenates have been carried out by selective ion detection with a gas chromatographic-mass spectrometric-computer system operated in the chemical ionization mode. Stable isotope labeled drugs were used as internal standards for quantification. The half-lives, the concentration at zero time, the slope (regression coefficient), the maximum velocity of the reaction and the apparent Michaelis constant of the reaction were determined by regression analysis, and also by graphic means.

Perioperative pharmacokinetics of methadone in adolescents.

PubMed

Sharma, Anshuman; Tallchief, Danielle; Blood, Jane; Kim, Thomas; London, Amy; Kharasch, Evan D

2011-12-01

Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed. Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone. The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients. Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.

Repaglinide pharmacokinetics in healthy young adult and elderly subjects.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

PubMed Central

Kumpulainen, Elina; Välitalo, Pyry; Kokki, Merja; Lehtonen, Marko; Hooker, Andrew; Ranta, Veli-Pekka; Kokki, Hannu

2010-01-01

AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h−1 70 kg−1. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (Vss) was 8.1 l 70 kg−1. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants. PMID:20840447

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

PubMed Central

Vuong, Chau; Xie, Lisa H.; Potter, Brittney M. J.; Zhang, Jing; Zhang, Ping; Duan, Dehui; Nolan, Christina K.; Sciotti, Richard J.; Zottig, Victor E.; Nanayakkara, N. P. Dhammika; Tekwani, Babu L.; Walker, Larry A.; Smith, Philip L.; Paris, Robert M.; Read, Lisa T.; Li, Qigui; Pybus, Brandon S.; Sousa, Jason C.; Reichard, Gregory A.; Smith, Bryan

2015-01-01

Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYPmouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations. PMID:25870069

Study design and implementation for population pharmacokinetics of Chinese medicine: An expert consensus.

PubMed

Jiang, Jun-jie; Zhang, Wen; Xie, Yan-ming; Wang, Jian-nong; He, Fu-yuan; Xiong, Xin

2016-02-01

Although many population pharmacokinetics (PPK) researches have been conducted on chemical drugs, few have been in the field of Chinese medicine (CM). Each ingredient in CMs possesses different pharmacokinetic characteristics, therefore, it is important to develop methods of PPK studies on them to identify the differences in CM drug safety and efficacy among the population subgroups and to conduct quantitative studies on the determinants of CM drug concentrations. To develop an expert consensus on study design and implementation for PPK of CM, in August 2013, 6 experts in the field of PPK, CMs pharmacology, and statistics discussed problems on the PPK research protocol of CMs, and a consensus was reached. The medicines with toxicity and narrow therapeutic windows and with wide range of target population or with frequent adverse reactions were selected. The compositions with definite therapeutic effects were selected as indices, and specific time points and sample sizes were designed according to standard PPK design methods. Target components were tested through various chromatography methods. Total quantity statistical moment analysis was used to estimate PPK parameters of each component and PPK models reflecting the trend of CMs (which assists in reasonable adjustments on clinical dosage). This consensus specifies the study design and implementation process of PPK. It provides guidance for the following: post-marketing clinical studies, in vivo investigations related to the metabolism in different populations, and development and clinical adjustment of dosages of CMs.

Magnesium sulphate for prevention of eclampsia: are intramuscular and intravenous regimens equivalent? A population pharmacokinetic study.

PubMed

Salinger, D H; Mundle, S; Regi, A; Bracken, H; Winikoff, B; Vicini, P; Easterling, T

2013-06-01

To compare magnesium sulphate concentrations achieved by intramuscular and intravenous regimens used for the prevention of eclampsia. Low-resource obstetric hospitals in Nagpur and Vellore, India. Pregnant women at risk for eclampsia due to hypertensive disease. A pharmacokinetic study was performed as part of a randomised trial that enrolled 300 women comparing intramuscular and intravenous maintenance regimens of magnesium dosing. Data from 258 enrolled women were analysed in the pharmacokinetic study. A single sample was drawn per woman with the expectation of using samples in a pooled data analysis. Pharmacokinetic parameters of magnesium distribution and clearance. Magnesium clearance was estimated to be 48.1 dl/hour, volume of distribution to be 156 dl and intramuscular bioavailability to be 86.2%. The intramuscular regimen produced higher initial serum concentrations, consistent with a substantially larger loading dose. At steady state, magnesium concentrations in the intramuscular and intravenous groups were comparable. With either regimen, a substantial number of women would be expected to have serum concentrations lower than those generally held to be therapeutic. Clinical implications were that a larger loading dose for the intravenous regimen should be considered; where feasible, individualised dosing of magnesium sulphate would reduce the variability in serum concentrations and might result in more women with clinically effective magnesium concentrations; and lower dose magnesium sulphate regimens should be considered with caution. © 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.

Pharmacokinetic analysis of 14C-ursodiol in newborn infants using accelerator mass spectrometry.

PubMed

Gordi, Toufigh; Baillie, Rebecca; Vuong, Le T; Abidi, Saira; Dueker, Stephen; Vasquez, Herbert; Pegis, Priscilla; Hopper, Andrew O; Power, Gordon G; Blood, Arlin B

2014-09-01

Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of (14) C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of (14) C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants. Five non-cholestatic infants were administered 3 consecutive oral microdoses of (14) C-ursodiol: 8 ng (1.0 nCi), 26 ng (3.3 nCi), and 80 ng (10 nCi) 48 hours apart. Three additional infants with cholestasis were administered a single 80 ng (10.0 nCi) oral dose of (14) C-ursodiol together with a therapeutic dose of 40 mg/kg of non-labeled ursodiol. A pharmacokinetic model describing ursodiol concentrations was developed using nonlinear mixed-effects modeling. The pharmacokinetics of ursodiol in this pilot study were best described by a two-compartment model with first-order elimination. This study demonstrates the feasibility and utility of microdose and microtrace methodology in pediatric research. © 2014, The American College of Clinical Pharmacology.

An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer.

PubMed

Lu, Dan; Joshi, Amita; Wang, Bei; Olsen, Steve; Yi, Joo-Hee; Krop, Ian E; Burris, Howard A; Girish, Sandhya

2013-08-01

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate recently approved by the US Food and Drug Administration for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. It comprises the microtubule inhibitory cytotoxic agent DM1 conjugated to the HER2-targeted humanized monoclonal antibody trastuzumab via a stable linker. To characterize the pharmacokinetics of T-DM1 in patients with metastatic breast cancer, concentrations of multiple analytes were quantified, including serum concentrations of T-DM1 conjugate and total trastuzumab (the sum of conjugated and unconjugated trastuzumab), as well as plasma concentrations of DM1. The clearance of T-DM1 conjugate is approximately 2 to 3 times faster than its parent antibody, trastuzumab. However, the clearance pathways accounting for this faster clearance rate are unclear. An integrated population pharmacokinetic model that simultaneously fits the pharmacokinetics of T-DM1 conjugate and total trastuzumab can help to elucidate the clearance pathways of T-DM1. The model can also be used to predict total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data, thereby reducing the frequency of pharmacokinetic sampling. T-DM1 conjugate and total trastuzumab serum concentration data, including baseline trastuzumab concentrations prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab

Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study.

PubMed

Semvua, Hadija H; Mtabho, Charles M; Fillekes, Quirine; van den Boogaard, Jossy; Kisonga, Riziki M; Mleoh, Liberate; Ndaro, Arnold; Kisanga, Elton R; van der Ven, Andre; Aarnoutse, Rob E; Kibiki, Gibson S; Boeree, Martin J; Burger, David M

2013-01-01

To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients. This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART). A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported. Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

Effect of pregnancy on the pharmacokinetics of paclitaxel: a case report.

PubMed

Lycette, Jennifer L; Dul, Carrie L; Munar, Myrna; Belle, Donna; Chui, Stephen Y; Koop, Dennis R; Nichols, Craig R

2006-10-01

Breast cancer during pregnancy is increasingly common as women delay childbearing until later in life. Safe administration of adjuvant chemotherapy during pregnancy has been reported. Physiologic and metabolic changes during pregnancy could alter the pharmacokinetics of these agents. This is a pilot study to prospectively study the pharmacokinetics of chemotherapeutic agents during pregnancy. Herein, we report the initial results with paclitaxel in the first patient.

Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies.

PubMed

Martin, Paul; Cheung, S Y Amy; Yen, Mark; Han, David; Gillen, Michael

2016-01-01

The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. Mean maximum plasma concentration (C max) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.

Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view.

PubMed

Chatterjee, Bappaditya; Hamed Almurisi, Samah; Ahmed Mahdi Dukhan, Ather; Mandal, Uttam Kumar; Sengupta, Pinaki

2016-11-01

Self-emulsifying drug delivery system (SEDDS) is an isotropic mixture of lipid, surfactant and co-surfactant, which forms a fine emulsion when comes in contact of an aqueous medium with mild agitation. SEDDS is considered as a potential platform for oral delivery of hydrophobic drug in order to overcome their poor and irregular bioavailability challenges. In spite of fewer advantages like improved solubility of drug, bypassing lymphatic transport etc., SEDDS faces different controversial issues such as the use of appropriate terminology (self-microemulsifying drug delivery system; SMEDDS or self-nanoemulsifying drug delivery system; SNEDDS), presence of high amount of surfactant, correlation of in vitro model to in vivo studies, lack of human volunteer study and effect of conversion of SEDDS to final administrable dosage form on pharmacokinetic behavior of the drug. In this review, potential issues or questions on SEDDS are identified and summarized from the pharmacokinetic point of view. Primarily this review includes the conflict between the influences of droplet size, variation in correlation between in vitro lipolysis or ex-vivo intestinal permeation and pharmacokinetic parameters, variation in in vivo results of solid and liquid SEDDS, and potential challenges or limitation of pharmacokinetic studies on human volunteers with orally administered SEDDS. In the past decades, hundreds of in vivo studies on SEDDS have been published. In the present study, only the relevant article on in vivo pharmacokinetic studies with orally administered SEDDS published in past 5-6 years are analyzed for an up to date compilation.

ISONIAZID AND RIFAMPIN PHARMACOKINETICS IN TWO ASIAN ELEPHANTS (ELEPHAS MAXIMUS) INFECTED WITH MYCOBACTERIUM TUBERCULOSIS.

PubMed

Egelund, Eric F; Isaza, Ramiro; Alsultan, Abdullah; Peloquin, Charles A

2016-09-01

This report describes the pharmacokinetic profiles of chronically administered oral isoniazid and rifampin in one adult male and one adult female Asian elephant ( Elephas maximus ) that were asymptomatically infected with Mycobacterium tuberculosis . Rifampin's half-life was reduced when compared to previous single-dose pharmacokinetic profiles of healthy uninfected Asian elephants. Both elephants experienced delayed absorption of isoniazid and rifampin as compared to previous pharmacokinetic studies in this species. The altered pharmacokinetics of both drugs in repeated-dosing clinical situations underscores the need for individual therapeutic drug monitoring for tuberculosis treatment.

A PHARMACOKINETIC PROGRAM (PKFIT) FOR R

EPA Science Inventory

The purpose of this study was to create a nonlinear regression (including a genetic algorithm) program (R script) to deal with data fitting for pharmacokinetics (PK) in R environment using its available packages. We call this tool as PKfit.

Single-dose pharmacokinetic study of 13-cis-retinoic acid in man.

PubMed

Besner, J G; Leclaire, R; Band, P; Meloche, S; Deschamps, M; Mailhot, S; Moisan, R; Diorio, G

1985-03-01

A pharmacokinetic study of 13-cis-retinoic acid was performed in nine patients following administration of a single oral dose of 80 mg. An average lag time of 1.2 hours was observed, followed by fast absorption, with a mean half-life of 0.5 hour. Peak plasmatic concentration of 733 ng/ml occurred at 2.3 hours. The disposition profile showed a rapid distribution half-life of 1.3 hours and a terminal elimination half-life of 24.7 hours. No 13-cis-retinoic acid was detected unchanged in urine. An important interpatient variability was noted.

Disposition pathways and pharmacokinetics of herbal medicines in humans.

PubMed

He, S-M; Li, C G; Liu, J-P; Chan, E; Duan, W; Zhou, S-F

2010-01-01

Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a

AFOSR Indo-UK -US Joint Physics Initiative for Study of Angular Optical Mode Fiber Amplification

DTIC Science & Technology

2017-02-20

AFRL -AFOSR-UK-TR-2017-0011 AFOSR Indo-UK -US Joint Physics Initiative for study of angular optical mode fiber amplification Johan Nilsson UNIVERSITY...ES) EOARD Unit 4515 APO AE 09421-4515 10. SPONSOR/MONITOR’S ACRONYM(S) AFRL /AFOSR IOE 11. SPONSOR/MONITOR’S REPORT NUMBER(S) AFRL -AFOSR-UK-TR-2017-0011...this travel, he had the opportunity to visit the Kirtland Air Force Base and interact with Dr Leanne Henry as well as Dr Iyad Dajani to discuss

Hollow Fiber Methodology for Pharmacokinetic/Pharmacodynamic Studies of Antimalarial Compounds

PubMed Central

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

2016-01-01

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

Population pharmacokinetics of phenytoin in critically ill children.

PubMed

Hennig, Stefanie; Norris, Ross; Tu, Quyen; van Breda, Karin; Riney, Kate; Foster, Kelly; Lister, Bruce; Charles, Bruce

2015-03-01

The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration. © 2014, The American College of Clinical Pharmacology.

Usefulness and pharmacokinetic study of oral terbinafine for hyperkeratotic type tinea pedis.

PubMed

Kikuchi, Izumi; Tanuma, Hiroyuki; Morimoto, Kensuke; Kawana, Seiji

2008-01-01

To study and establish an optimal administration method of oral antifungal, terbinafine (TBF), for hyperkeratotic type tinea pedis, from the pharmacokinetic point of view, 20 patients with hyperkeratotic type tinea pedis were given TBF 125 mg once daily for 4 weeks and observed over time for improvement in dermatological symptoms and mycological efficacy. Targeting five of the patients, TBF concentration in the stratum corneum was measured using the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. TBF was detected in the stratum corneum of the sole 1 week after beginning the treatment in some cases and reached its peak 1 week after the completion of the treatment with a concentration of 247.8 ng g(-1), which was approximately more than 50 times higher than its minimal inhibitory concentration against dermatophytes. TBF was not detected at 8 weeks post-treatment, although its concentration was 50.73 ng g(-1) at 6 weeks post-treatment. Its effectiveness rate (effective + markedly effective) was 95% (19/20) with no adverse reactions, including abnormal changes in the laboratory test values, in any patient. These results suggest that TBF is a useful drug to treat hyperkeratotic tinea pedis from the pharmacokinetic point of view.

[Pharmacokinetic research strategies of compatibilities and synergistic effects of classical Danshen herb pairs based on pharmacokinetics of "Danshen-Bingpian" and "Danshen-Honghua"].

PubMed

Zhang, Cui-Ying; Ren, Wei-Guang

2017-06-01

Herb pairs are usual clinical compatibility forms and one of compound prescription sources in Chinese medicine. Pharmacokinetic research in vivo is one of the important items in elucidating the mechanism for synergistic and attenuated mechanisms of herb pairs. The paper comprehensively summarized and systemized the pharmacokinetic researches of marker-ingredients about Danshen-Honghua and Danshen-Bingpian in order to elucidate the rationality and scientificity of herb pairs and provide some feasible suggestions on the pharmacokinetics of drugs in the future. In view of complicated system of Traditional Chinese medicines and a chemical system that is not separated from its natural state, comparative pharmacokinetic researches on marker-ingredients from the herb pairs are reasonable to elucidate the synergistic and attenuated mechanisms of monarch-subjects compatible herbs and monarch-guide compatible herbs. Such pharmacokinetic research can better explain the mechanism of drug compatibility, while the pharmacokinetic researches based on the monomer chemical compositions and marker-ingredients that have been separated from complex chemical environment of traditional Chinese Medicine are still unreasonable and should be discussed deeply. Copyright© by the Chinese Pharmaceutical Association.

Pharmacokinetic studies of active triterpenoid saponins and the total secondary saponin from Anemone raddeana Regel.

PubMed

Zhang, Dandan; Lei, Tianli; Lv, Chongning; Zhao, Huimin; Xu, Haiyan; Lu, Jincai

2017-02-15

The rhizome of Anemone raddeana Regel, a Traditional Chinese Medicine (TCM) which has a robust history treating rheumatism and neuralgia. The total secondary saponin (TSS) from it has demonstrated antitumor activity. In this study, a rapid and validated LC-MS/MS method was developed to simultaneously determine the active compounds (Hederacolchiside A1 and Eleutheroside K). Analytes were separated on a reverse-phase C18 column with acetonitrile-water (5mmol/L ammonium acetate) as the mobile phase. This assay showed acceptable linearity (r>0.99) over the concentration range 5-1000 nmol/L for two analytes. The intra- and inter-day precision was within 8.06% and accuracy was ranged from -3.16% to 3.34% for two analytes. The mean extraction recoveries of analytes and IS from rat plasma were all more than 76.0%. Under the developed analytical conditions, the obtained values of main pharmacokinetic parameters (C max and AUC 0-t ) indicated that the pure compounds were more efficient than the TSS extract in Hederacolchiside A1 and Eleutheroside K absorption. In addition, pharmacokinetic studies of two individual compounds demonstrated their poor oral absorption in rat ( a F%, 0.019-1.521). In the study of absorption and transportation of Hederacolchiside A1 and Eleutheroside K in Caco-2 cell monolayer model, the uptake permeability was in 10 -6 cm/sec range suggesting poor absorption, which confirmed the previous pharmacokinetic profiles in vivo. Interestingly, the uptake ratio of them declined significantly when treated with phloridzin (SGLT1 inhibitor). It indicated that the absorption of Hederacolchiside A1 in intestine was mainly through positive transport and SGLT1 might participate in its active absorption. Copyright © 2017 Elsevier B.V. All rights reserved.

Dosing antibiotics in neonates: review of the pharmacokinetic data.

PubMed

Rivera-Chaparro, Nazario D; Cohen-Wolkowiez, Michael; Greenberg, Rachel G

2017-09-01

Antibiotics are often used in neonates despite the absence of relevant dosing information in drug labels. For neonatal dosing, clinicians must extrapolate data from studies for adults and older children, who have strikingly different physiologies. As a result, dosing extrapolation can lead to increased toxicity or efficacy failures in neonates. Driven by these differences and recent legislation mandating the study of drugs in children and neonates, an increasing number of pharmacokinetic studies of antibiotics are being performed in neonates. These studies have led to new dosing recommendations with particular consideration for neonate body size and maturation. Herein, we highlight the available pharmacokinetic data for commonly used systemic antibiotics in neonates.

Population pharmacokinetic modeling and simulation of huperzine A in elderly Chinese subjects

PubMed Central

Sheng, Lei; Qu, Yi; Yan, Jing; Liu, Gang-yi; Wang, Wei-liang; Wang, Yi-jun; Wang, Hong-yi; Zhang, Meng-qi; Lu, Chuan; Liu, Yun; Jia, Jing-yin; Hu, Chao-ying; Li, Xue-ning; Yu, Chen; Xu, Hong-rong

2016-01-01

Aim: Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration. Methods: A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models. Results: The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649*(age/86)(−3.3856), Ka=0.6750 h−1, V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks. Conclusion: A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients. PMID:27180987

The hospital microbiome project: meeting report for the UK science and innovation network UK-USA workshop ‘beating the superbugs: hospital microbiome studies for tackling antimicrobial resistance’, October 14th 2013

PubMed Central

2014-01-01

The UK Science and Innovation Network UK-USA workshop ‘Beating the Superbugs: Hospital Microbiome Studies for tackling Antimicrobial Resistance’ was held on October 14th 2013 at the UK Department of Health, London. The workshop was designed to promote US-UK collaboration on hospital microbiome studies to add a new facet to our collective understanding of antimicrobial resistance. The assembled researchers debated the importance of the hospital microbial community in transmission of disease and as a reservoir for antimicrobial resistance genes, and discussed methodologies, hypotheses, and priorities. A number of complementary approaches were explored, although the importance of the built environment microbiome in disease transmission was not universally accepted. Current whole genome epidemiological methods are being pioneered in the UK and the benefits of moving to community analysis are not necessarily obvious to the pioneers; however, rapid progress in other areas of microbiology suggest to some researchers that hospital microbiome studies will be exceptionally fruitful even in the short term. Collaborative studies will recombine different strengths to tackle the international problems of antimicrobial resistance and hospital and healthcare associated infections.

Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid

PubMed Central

Lee, Soo-Yun; Huh, Wooseong; Jung, Jin Ah; Yoo, Hye Min; Ko, Jae-Wook; Kim, Jung-Ryul

2015-01-01

Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; Cmax, 52.1 mg/L vs 53.0 mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and Cmax (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary. PMID:26309401

Pharmacokinetics and Pharmacodynamics of Oximes in Unanesthetized Pigs

DTIC Science & Technology

1991-04-01

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

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs: A pilot study

PubMed Central

Larson, Jeanne C.; Allstadt, Sara D.; Fan, Timothy M.; Khanna, Chand; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.; Legendre, Alfred M.; Galyon, Gina D.; LeBlanc, Amy K.; Martin-Jimenez, Tomas

2017-01-01

Objective To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. Animals 5 healthy purpose-bred hounds. Procedures The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and non-compartmental analyses. Results Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. Conclusions and Clinical Relevance Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in ng/mL. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, needs to be determined. PMID:26709938

Applied Pharmacokinetics: Course Description and Retrospective Evaluation.

ERIC Educational Resources Information Center

Beck, Diane E.

1984-01-01

An applied course designed to allow students to formulate pharmacokinetic recommendations individually for actual patient data and compare their recommendations to those of a pharmacokinetic consulting service is described and evaluated, and an objective student evaluation method is outlined. (MSE)

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

PubMed

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

2017-06-01

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

Prophylactic ranitidine treatment in critically ill children--a population pharmacokinetic study.

PubMed

Hawwa, Ahmed F; Westwood, Paul M; Collier, Paul S; Millership, Jeffrey S; Yakkundi, Shirish; Thurley, Gillian; Shields, Mike D; Nunn, Anthony J; Halliday, Henry L; McElnay, James C

2013-05-01

To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs

PubMed Central

Paoloni, Melissa C.; Mazcko, Christina; Fox, Elizabeth; Fan, Timothy; Lana, Susan; Kisseberth, William; Vail, David M.; Nuckolls, Kaylee; Osborne, Tanasa; Yalkowsy, Samuel; Gustafson, Daniel; Yu, Yunkai; Cao, Liang; Khanna, Chand

2010-01-01

Background Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients. Methodology/Principal Findings This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy. Conclusions/Significance Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and

Differential cytochrome P450 2D metabolism alters tafenoquine pharmacokinetics.

PubMed

Vuong, Chau; Xie, Lisa H; Potter, Brittney M J; Zhang, Jing; Zhang, Ping; Duan, Dehui; Nolan, Christina K; Sciotti, Richard J; Zottig, Victor E; Nanayakkara, N P Dhammika; Tekwani, Babu L; Walker, Larry A; Smith, Philip L; Paris, Robert M; Read, Lisa T; Li, Qigui; Pybus, Brandon S; Sousa, Jason C; Reichard, Gregory A; Smith, Bryan; Marcsisin, Sean R

2015-07-01

Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYPmouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Biodistribution of the Illegal Food Colorant Rhodamine B in Rats.

PubMed

Cheng, Yung-Yi; Tsai, Tung-Hu

2017-02-08

The International Agency for Research on Cancer (IARC) demonstrated rhodamine B as a potential carcinogen in 1978. Nevertheless, rhodamine B has been illegally used as a colorant in food in many countries. Few pharmacokinetic and toxicological investigations have been performed since the first pharmacokinetic study on rhodamine B in 1961. The aims of this study were to develop a simple and sensitive high-performance liquid chromatography method with fluorescence detection for the quantitative detection of rhodamine B in the plasma and organs of rats and to estimate its pharmacokinetics and biodistribution. The results demonstrated that the oral bioavailabilities of rhodamine B were 28.3 and 9.8% for the low-dose and high-dose exposures, respectively. Furthermore, rhodamine B was highly accumulated in the liver and, to a lesser extent, the kidney, but was undetectable in the brain. These results provide useful information for improving the pharmacokinetics and biodistribution of rhodamine B, supporting additional food safety evaluations.

Impact of body composition on pharmacokinetics of doxorubicin in children: A Glaser Pediatric Research Network study

USDA-ARS?s Scientific Manuscript database

We studied the relationship between doxorubicin pharmacokinetics and body composition in children with cancer. Children between 1 and 21 years of age, receiving doxorubicin as an infusion of any duration <24 h on either a 1-day or 2-day schedule, were eligible if they had no significant abnormality ...

META-ANALYSIS OF CYP2D6 METABOLIZER PHENOTYPE AND METOPROLOL PHARMACOKINETICS

PubMed Central

Blake, CM; Kharasch, ED; Schwab, M; Nagele, P

2013-01-01

Metoprolol, a commonly prescribed beta-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate release metoprolol was performed. Pooled analysis (n= 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration-time curve, elimination half-life, and apparent oral clearance that were 2.3-, 4.9-, 2.3-, and 5.9-fold between extensive and poor metabolizers, respectively, and 5.3-, 13-, 2.6-, and 15-fold between ultra-rapid and poor metabolizers (all p<0.001). Enantiomer-specific analysis revealed genotype-dependent enantio-selective metabolism, with nearly 40% greater R- vs S-metoprolol metabolism in ultra-rapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer specific metabolism of metoprolol. PMID:23665868

The (mis)management of migrant nurses in the UK: a sociological study.

PubMed

Adhikari, Radha; Melia, Kath M

2015-04-01

To examine Nepali migrant nurses' professional life in the UK. In the late 1990 s the UK experienced an acute nursing shortage. Within a decade over 1000 Nepali nurses migrated to the UK. A multi-sited ethnographic approach was chosen for this study. Between 2006 and 2009, 21 in-depth interviews with Nepali nurses were conducted in the UK using snowballing sampling. Nepali migrant nurses are highly qualified and experienced in specialised areas such as critical care, management and education. However, these nurses end up working in the long-term care sector, providing personal care for elderly people - an area commonly described by migrant nurses as British Bottom Care (BBC). This means that migrant nurses lack career choices and professional development opportunities, causing them frustration and lack of job satisfaction. International nurse migration is an inevitable part of globalisation in health. Nurse managers and policy makers need to explore ways to make better use of the talents of the migrant workforce. We offer a management strategy to bring policies for the migrant workforce into line with the wider workforce plans by supporting nurses in finding jobs relevant to their expertise and providing career pathways. © 2013 John Wiley & Sons Ltd.

Perioperative pharmacokinetics of ibuprofen enantiomers after rectal administration.

PubMed

Kyllönen, Matti; Olkkola, Klaus T; Seppälä, Timo; Ryhänen, Pauli

2005-07-01

Ibuprofen is a nonsteroidal anti-inflammatory drug which has both peripheral and central analgesic effects. Ibuprofen has been shown to be an effective antipyretic and postoperative analgesic drug both in adults and children with few side effects. Pharmacokinetics of rectal ibuprofen has not been studied, although suppositories are frequently used for perioperative pain control in children. There were four study groups: full-term infants aged 1-7 weeks (n = 9), infants aged 8-25 weeks (n = 8), and infants aged 26-52 weeks (n = 7). Adult patients were 20-40 years old (n = 7). Ibuprofen suppository 20 mg.kg(-1) was administered after induction of anesthesia. Blood samples were collected from 20 min to 10 h after dosing and pharmacokinetic analysis of ibuprofen enantiomers were done. Both ibuprofen enantiomers were detectable in blood in 20 min. Total ibuprofen plasma concentrations >10 mg.l(-1) were seen from 40 min to 8 h. Values for T(max) of ibuprofen enantiomers and total ibuprofen were higher in the adult group than any of the infant groups (P < 0.05). In addition, values for physiological (standardized) t(1/2) of (R)-(-)- and (S)-(+)-ibuprofen were higher in infants aged 1-7 weeks than the adults (P < 0.05). None of the other pharmacokinetic variables, C(max), AUC, chronological t(1/2) or AUC ratio differed between the groups. A single dose of ibuprofen suppository 20 mg.kg(-1) after induction of anesthesia guarantees analgesic plasma concentrations during the early postoperative period. Except for the delayed absorption of ibuprofen in adults and higher physiological t(1/2) in infants aged 1-7 weeks, no major pharmacokinetic differences were observed between study groups.

Metabolic pathways and pharmacokinetics of natural medicines with low permeability.

PubMed

Zeng, Mei; Yang, Lan; He, Dan; Li, Yao; Shi, Mingxin; Zhang, Jingqing

2017-11-01

Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine.

Utilizing the Peer Group Method with Case Studies to Teach Pharmacokinetics.

ERIC Educational Resources Information Center

Sims, Pamela J.

1994-01-01

A pharmacy school large-group (110 students) course in pharmacokinetics was designed to incorporate small-group team-based problem solving. The method allows students to learn material through traditional lecture, research the topic further, discuss the information gained, and apply the learning to specific cases in a manner that promotes…

International Students' Networks: A Case Study in a UK University

ERIC Educational Resources Information Center

Taha, Nashrawan; Cox, Andrew

2016-01-01

The great influx of international students into UK universities has led to internationalisation becoming an important issue. Previous studies have focused on the integration of home and international students, illustrating a lack of intercultural interaction. Yet there has been a lack of research investigating international students' networks and…

Pharmacokinetic variations in cancer patients with liver dysfunction: applications and challenges of pharmacometabolomics.

PubMed

Aboel Dahab, Ali; El-Hag, Dhia; Moutamed, Gamal M; Aboel Dahab, Sarah; Abuknesha, Ramadan; Smith, Norman W

2016-09-01

In cancer patients, pharmacokinetic variations between individuals and within individuals due to impairments in organs' function and other reasons such as genetic polymorphisms represent a major problem in disease management, which can result in unpredictable toxicity and variable antineoplastic effects. Addressing pharmacokinetic variations in cancer patients with liver dysfunction and their implications on anticancer and analgesic drugs, in addition to the use of advanced analytical techniques such as metabolomics and pharmacometabolomics, to monitor altered kinetic and discover metabolic biomarkers during therapeutic intervention will help in understanding and reducing pharmacokinetic variations of drugs in cancer patients as a step forward towards personalised medicine. Reviewing published literature addressing and/or related to complications resulting from altered pharmacokinetics (PKs) in cancer patients with liver dysfunction, anticancer and analgesic drugs, evaluating recent advances of pharmacokinetic detection using metabolomics/pharmacometabolomics and the challenges that are currently facing these techniques. The current situation presents a pressing need to reduce pharmacokinetic variations of drugs in cancer patients. Although most of the omics technologies are not entirely focussed on the study of pharmacokinetic variations and some studies are met with uncertainty, the use of pharmacometabolomics combined with other omics technology such as pharmacogenomics can provide clues to personalised cancer treatments by providing useful information about the cancer patient's response to medical interventions via identification of patients' dependent variables, understanding of correlations between individuals and population PKs, and therapy outcomes to achieve optimum therapeutic effects with minimum toxicity. We also propose an approach for PKs' evaluation using pharmacometabolomics.

Pharmacokinetics of intravenous levofloxacin administered at 750 milligrams in obese adults.

PubMed

Cook, Aaron M; Martin, Craig; Adams, Val R; Morehead, R Scott

2011-07-01

The physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing.

Predicting Age-appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically-based Pharmacokinetic Modeling (T)

EPA Science Inventory

The capability of physiologically-based pharmacokinetic (PBPK) models to incorporate ageappropriate physiological and chemical-specific parameters was utilized in this study to predict changes in internal dosimetry for six volatile organic compounds (VOCs) across different ages o...

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

PubMed

Kobuchi, Shinji; Ito, Yukako; Sakaeda, Toshiyuki

2017-08-01

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

Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs.

PubMed

KuKanich, Butch; KuKanich, Kate

2015-11-01

To assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in Greyhound dogs to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs. Non-randomized, sequential design. Six healthy Greyhound dogs (three male, three female). Canine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection. Significant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX ) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng mL(-1)) and CMAX (6 ng mL(-1)) of methadone significantly increased to 541 hours ng mL(-1) and 47.8 ng mL(-1), respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction. This study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Isolation, characterization, and in rats plasma pharmacokinetic study of a new triterpenoid saponin from Dianthus superbus.

PubMed

Ren, Yina; Xu, Xiaobao; Zhang, Qianlan; Lu, Yongzhuang; Li, Ximin; Zhang, Lin; Tian, Jingkui

2017-02-01

One new oleanolic acid triterpenoid saponin, 3-O-β-D-glucopyranosyl olean-11, 13(18)-diene-23,28-dioic acid, (hereafter referred to as DS-1) was isolated from the traditional Chinese medicinal plant Dianthus superbus (D. superbus). DS-1 plays an important role in the bioactivity of D. superbus. Thus, a sensitive, reliable and accurate reversed-phased liquid chromatography with tandem mass spectrometry (LC-MS/MS) in negative ion mode was developed and validated for the quantification and pharmacokinetic study of DS-1 in rats plasma. The pharmacokinetic profile showed that DS-1 was rapidly absorbed and eliminated in plasma, indicating that significant accumulation of the compound in biological specimen is unlikely. In addition, poor absorption into systemic circulation was observed after oral administration of DS-1, resulting in low absolute bioavailability (0.92 %).

Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

PubMed

Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

2014-11-01

Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses.

Ethanol Pharmacokinetics in Neonates and Infants

PubMed Central

Marek, Elizabeth; Kraft, Walter K.

2014-01-01

Introduction Ethanol has been used for years in neonatal and infant liquid medications, yet the pharmacokinetics, pharmacodynamics, and safety of ethanol in this vulnerable population have not been well characterized. The purpose of this review is to raise awareness of ethanol use as an excipient in neonatal and infant medications and to provide insight, based on the available evidence, into clearance rates of ethanol in babies. We also discuss ethanol pharmacokinetics in adults, theoretical pharmacokinetic changes in neonates and infants as it may apply to ethanol disposition, and case reports involving ethanol exposure in neonates and infants. Materials and methods This study was a narrative review in which relevant papers were selected using databases and scientific search engines such as PubMed with the key words ethanol, infant, and newborninfant. Results It remains unclear what ethanol exposure is safe for neonates and infants. The Food and Drug Administration and American Academy of Pediatrics have both taken action, by either setting limits of ethanol content in over-the-counter medications or by recommending restricted exposure to ethanol-containing pediatric formulations. Conclusions Until the short- and long-term health effects of chronic ethanol administration can be further characterized, ethanol-containing medications should be used with caution. PMID:25379066

Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies.

PubMed

Chew, Marci L; Plotka, Anna; Alvey, Christine W; Pitman, Verne W; Alebic-Kolbah, Tanja; Scavone, Joseph M; Bockbrader, Howard N

2014-09-01

The pharmacokinetic properties of the immediate-release (IR) and the recently developed controlled-release (CR) formulation of pregabalin are dose proportional. Pregabalin IR can be taken with or without food. This analysis characterizes the effect of food on pregabalin CR. The objectives of this analysis were: (1) to evaluate the effect of administration time and fat or caloric content of an accompanying meal on the pharmacokinetic properties of a single dose of pregabalin CR (330 mg) relative to a single dose of pregabalin IR (300 mg); (2) to evaluate the pharmacokinetic properties of a single dose of pregabalin CR administered fasted relative to a single dose of pregabalin CR administered immediately after food; and (3) to determine the safety and tolerability of single-dose administration of pregabalin CR and IR with and without food. The effect of food on the pharmacokinetic properties of pregabalin CR was determined in five phase I, open-label, single-dose, crossover studies (24-28 participants/study). Caloric and fat content of meals were varied and treatments were administered in the morning, at midday, or in the evening. Blood samples were collected up to 48 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. One hundred and twenty-eight healthy participants (19-54 years of age) received pregabalin. Peak plasma concentrations (C max) were lower for CR than the respective pregabalin IR doses, and time to C max occurred later. When pregabalin CR was administered with food at midday or in the evening, total exposures [area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC∞)] were equivalent for pregabalin CR and IR formulations regardless of fat or caloric content. When pregabalin CR was administered with an 800-1,000 calorie medium-fat breakfast, AUC∞ was equivalent for

Mapping allergenic pollen vegetation in UK to study environmental exposure and human health.

PubMed

McInnes, Rachel N; Hemming, Deborah; Burgess, Peter; Lyndsay, Donna; Osborne, Nicholas J; Skjøth, Carsten Ambelas; Thomas, Sam; Vardoulakis, Sotiris

2017-12-01

Allergenic pollen is produced by the flowers of a number of trees, grasses and weeds found throughout the UK. Exposure to such pollen grains can exacerbate pollen-related asthma and allergenic conditions such as allergic rhinitis (hay fever). Maps showing the location of these allergenic taxa have many applications: they can be used to provide advice on risk assessments; combined with health data to inform research on health impacts such as respiratory hospital admissions; combined with weather data to improve pollen forecasting systems; or as inputs to pollen emission models. In this study we present 1km resolution maps of 12 taxa of trees, grass and weeds found in the UK. We have selected the main species recorded by the UK pollen network. The taxa mapped in this study were: Alnus (alder), Fraxinus (ash), Betula (birch), Corylus (hazel), Quercus (oak), Pinus (pine) and Salix (willow), Poaceae (grass), Artemisia (mugwort), Plantago (plantain), Rumex (dock, sorrels) and Urtica (nettle). We also focus on one high population centre and present maps showing local level detail around the city of London. Our results show the different geographical distributions of the 12 taxa of trees, weeds and grass, which can be used to study plants in the UK associated with allergy and allergic asthma. These maps have been produced in order to study environmental exposure and human health, although there are many possible applications. This novel method not only provides maps of many different plant types, but also at high resolution across regions of the UK, and we uniquely present 12 key plant taxa using a consistent methodology. To consider the impact on human health due to exposure of the pollen grains, it is important to consider the timing of pollen release, and its dispersal, as well as the effect on air quality, which is also discussed here. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Population pharmacokinetic modeling of furosemide in patients with hypertension and fluid overload conditions.

PubMed

Kodati, Devender; Yellu, Narsimhareddy

2017-06-01

Furosemide is a loop diuretic drug frequently indicated in hypertension and fluid overload conditions such as congestive heart failure and hepatic cirrhosis. The purpose of the study was to establish a population pharmacokinetic model for furosemide in Indian hypertensive and fluid overload patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of furosemide. A total of 188 furosemide plasma sample concentrations from 63 patients with hypertension or fluid overload conditions were collected in this study. The population pharmacokinetic model for furosemide was built using Phoenix NLME 1.3 software. The covariates included age, sex, body surface area, bodyweight, height and creatinine clearance (CRCL). The pharmacokinetic data of furosemide was adequately explained by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and Vd/F of furosemide in the patients were 15.054Lh -1 and 4.419L, respectively. Analysis of covariates showed that CRCL was significantly influencing the clearance of furosemide. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of furosemide in Indian patients with hypertension and fluid overload conditions. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

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. © 2014, The American College of Clinical Pharmacology.

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

PubMed

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

2016-09-01

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

Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study

PubMed Central

Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José

2016-01-01

Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentration in vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

Emerging and legacy flame retardants in UK human milk and food suggest slow response to restrictions on use of PBDEs and HBCDD.

PubMed

Tao, Fang; Abou-Elwafa Abdallah, Mohamed; Ashworth, Danielle C; Douglas, Philippa; Toledano, Mireille B; Harrad, Stuart

2017-08-01

The legacy flame retardants (LFRs) polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD), together with six emerging flame retardants (EFRs) were measured in United Kingdom (UK) human milk collected in 2010 (n=25) and 2014-15 (n=10). These data are the first report of the presence of EFRs in UK human milk. The most abundant EFR was β-tetrabromoethylcyclohexane (DBE-DBCH) (average=2.5ng/g lw; geometric mean=1.5ng/g lw), which is comparable to the concentrations of the most abundant LFRs i.e. BDE 47 and α-HBCDD at 2.8 and 2.1ng/g lw, respectively (geometric mean=2.1 and 1.7). The estimated median dietary intake of ΣEFRs by UK nursing infants was 18ng/kg bw/day. EFRs were also measured in UK foodstuffs with β-DBE-DBCH again the predominant compound detected, accounting - on average - for 64.5±23.4% of ΣEFRs. Average estimated dietary intakes of ∑EFRs in the UK were 89 and 26ng/day (1.3 and 2.6ng/body weight/day) for adults and toddlers, respectively. Concentrations of Σtri-hexa BDEs in our UK food samples exceeded those reported in UK samples from the same food categories collected in 2003-04 and 2006. Despite this and our recent report elsewhere of significant temporal declines in concentrations of BDE 209 in UK indoor dust (p<0.05) and HBCDDs in UK indoor dust and air (p<0.001), no significant temporal differences (p>0.05) were observed between concentrations of Σtri-hexa BDEs, BDE 209 and HBCDDs in human milk sampled in 2010 and those obtained in 2014-15. UK adult body burdens for EFRs were predicted via inhalation, diet and dust ingestion using a simple pharmacokinetic model. The predicted EFR body burdens compared well with observed concentrations in human milk. Copyright © 2017 Elsevier Ltd. All rights reserved.

Trapped in Transition: Findings from a UK Study of Student Suicide

ERIC Educational Resources Information Center

Stanley, Nicky; Mallon, Sharon; Bell, Jo; Manthorpe, Jill

2009-01-01

This study of student suicide within UK higher education directs attention to the community context of suicide. A modified psychological autopsy approach was used to explore 20 case studies of student suicide from the period 2000-2005, drawing on the perspectives of family members, friends and university staff. The study identifies features of the…

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.

Pharmacokinetic interaction between scutellarin and valsartan in rats.

PubMed

Cui, Ming-Yu; Tian, Chong-Chong; Ju, Ai-Xia; Zhang, Chun-Ting; Li, Qiu-Hong

2013-04-01

Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).

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

PubMed Central

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

2015-01-01

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

Accelerated Brain DCE-MRI Using Iterative Reconstruction With Total Generalized Variation Penalty for Quantitative Pharmacokinetic Analysis: A Feasibility Study.

PubMed

Wang, Chunhao; Yin, Fang-Fang; Kirkpatrick, John P; Chang, Zheng

2017-08-01

To investigate the feasibility of using undersampled k-space data and an iterative image reconstruction method with total generalized variation penalty in the quantitative pharmacokinetic analysis for clinical brain dynamic contrast-enhanced magnetic resonance imaging. Eight brain dynamic contrast-enhanced magnetic resonance imaging scans were retrospectively studied. Two k-space sparse sampling strategies were designed to achieve a simulated image acquisition acceleration factor of 4. They are (1) a golden ratio-optimized 32-ray radial sampling profile and (2) a Cartesian-based random sampling profile with spatiotemporal-regularized sampling density constraints. The undersampled data were reconstructed to yield images using the investigated reconstruction technique. In quantitative pharmacokinetic analysis on a voxel-by-voxel basis, the rate constant K trans in the extended Tofts model and blood flow F B and blood volume V B from the 2-compartment exchange model were analyzed. Finally, the quantitative pharmacokinetic parameters calculated from the undersampled data were compared with the corresponding calculated values from the fully sampled data. To quantify each parameter's accuracy calculated using the undersampled data, error in volume mean, total relative error, and cross-correlation were calculated. The pharmacokinetic parameter maps generated from the undersampled data appeared comparable to the ones generated from the original full sampling data. Within the region of interest, most derived error in volume mean values in the region of interest was about 5% or lower, and the average error in volume mean of all parameter maps generated through either sampling strategy was about 3.54%. The average total relative error value of all parameter maps in region of interest was about 0.115, and the average cross-correlation of all parameter maps in region of interest was about 0.962. All investigated pharmacokinetic parameters had no significant differences between

Population pharmacokinetics of oxycodone in patients with cancer-related pain.

PubMed

Komatsu, Toshiaki; Kokubun, Hideya; Suzuki, Ai; Takayanagi, Risa; Yamada, Yasuhiko; Matoba, Motohiro; Yago, Kazuo

2012-09-01

Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

The comparative pharmacokinetic study of Yuanhu Zhitong prescription based on five quality-markers.

PubMed

Zhang, Hongbing; Wu, Xin; Xu, Jun; Gong, Suxiao; Han, Yanqi; Zhang, Tiejun; Liu, Changxiao

2018-02-21

According to the compatibility theory, therapeutic effects of Chinese medicine prescription are generally attributed to the synergism of multi-herbs. Quality-markers, as the crucial effective components, play a key role in the interaction of compatibility. Pharmacokinetic studies could illustrate the interaction between multiple components in dynamics perspective. This study aims to establish a rapid, reliable and sensitive ultra performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous determination of corydaline, tetrahydropalmatine, protopine, imperatorin and isoimperatorin (quality-markers of Yuanhu Zhitong prescription) in rat plasma, and then applied to the comparative pharmacokinetic study for clearing the interaction of compatibility in Yuanhu Zhitong prescription. Five quality-markers were separated on a Waters Acquity UPLC BEH C 18 column (2.1 mm × 50 mm, 1.7 µm) by gradient elution with 0.1% formic acid-water and 0.1% formic acid-acetonitrile. Detection was performed in the positive ionization and multiple reaction monitoring mode. The analytical method was validated and successfully applied to the comparative pharmacokinetic study after oral administration of Yuanhu Zhitong prescription and single-herb extracts. Calibration curves showed good linearity over the concentration ranges of 0.25-500 ng/ml for corydaline, tetrahydropalmatine and isoimperatorin, 0.1-200 ng/ml for protopine, and 0.5-500 ng/ml for imperatorin, respectively. Compared with Rhizoma corydalis group, AUC 0-t and AUC 0-∞ significantly increased (p < 0.01 for corydaline and tetrahydropalmatine, and p < 0.05 for protopine) after oral administration of Yuanhu Zhitong prescription extract. Meanwhile, C max of corydaline and tetrahydropalmatine increased remarkably, from 93.00 µg/l to 196.35 µg/l for corydaline (p < 0.05) and 181.62 µg/l to 311.22 µg/l for tetrahydropalmatine (p < 0.01). In addition, MRT 0

Drug Transport and Pharmacokinetics for Chemical Engineers

ERIC Educational Resources Information Center

Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

2010-01-01

Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV-1-Infected, Treatment-Experienced Children and Adolescents in PIANO.

PubMed

Kakuda, Thomas N; Brochot, Anne; Green, Bruce; Nijs, Steven; Vis, Peter; Opsomer, Magda; Tomaka, Frank L; Hoetelmans, Richard M W

2016-11-01

PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment-experienced, HIV-1-infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C 0h and AUC 0-12h were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero- and first-order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first-order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h -1 , respectively. Overall, median (range) estimated etravirine C 0h and AUC 0-12h were 287 (2-2276) ng/mL and 4560 (62-28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC 0-12h quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment-experienced, HIV-1-infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents. © 2016, The American College of Clinical Pharmacology.

PET studies of d-methamphetamine pharmacokinetics in primates: comparison with l-methamphetamine and ( --)-cocaine.

PubMed

Fowler, Joanna S; Kroll, Carsten; Ferrieri, Richard; Alexoff, David; Logan, Jean; Dewey, Stephen L; Schiffer, Wynne; Schlyer, David; Carter, Pauline; King, Payton; Shea, Colleen; Xu, Youwen; Muench, Lisa; Benveniste, Helene; Vaska, Paul; Volkow, Nora D

2007-10-01

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (-)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. d- and l-methamphetamine and (-)-cocaine were labeled with (11)C via alkylation of the norprecursors with (11)C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2-3 h apart to determine the distribution and kinetics of (11)C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. (11)C-d-Methamphetamine pharmacokinetics were compared with (11)C-l-methamphetamine and (11)C-(-)-cocaine in both brain and peripheral organs in the same animal. (11)C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. (11)C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of (11)C-d-methamphetamine and (11)C-(-)-cocaine showed that (11)C-d-methamphetamine peaked later in the brain than did (11)C-(-)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and

Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

PubMed Central

Paradisis, Mary; Jiang, Xuemin; McLachlan, Andrew J; Evans, Nick; Kluckow, Martin; Osborn, David

2007-01-01

Aims To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. Methods A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). Results Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. Conclusion Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology. PMID:16690639

An interactive program for pharmacokinetic modeling.

PubMed

Lu, D R; Mao, F

1993-05-01

A computer program, PharmK, was developed for pharmacokinetic modeling of experimental data. The program was written in C computer language based on the high-level user-interface Macintosh operating system. The intention was to provide a user-friendly tool for users of Macintosh computers. An interactive algorithm based on the exponential stripping method is used for the initial parameter estimation. Nonlinear pharmacokinetic model fitting is based on the maximum likelihood estimation method and is performed by the Levenberg-Marquardt method based on chi 2 criterion. Several methods are available to aid the evaluation of the fitting results. Pharmacokinetic data sets have been examined with the PharmK program, and the results are comparable with those obtained with other programs that are currently available for IBM PC-compatible and other types of computers.

Simultaneous determination of five components in rat plasma by UPLC-MS/MS and its application to a comparative pharmacokinetic study in Baihe Zhimu Tang and Zhimu extract.

PubMed

Li, Guolong; Tang, Zhishu; Yang, Jie; Duan, Jinao; Qian, Dawei; Guo, Jianming; Zhu, Zhenhua; Liu, Hongbo

2015-04-15

Baihe Zhimu Tang (BZT) is a famous traditional Chinese medicine recipe to treat dry coughing due to yin deficiency and for moisturizing the lungs. Zhimu is an essential ingredient in BZT used to treat inflammation, fever and diabetes. The most important active components in Zhimu are flavonoids such as neomangiferin, mangiferin, and steroid saponins (e.g., timosaponin BII, anemarsaponin BIII, timosaponin AIII). The aim of this study was to compare the pharmacokinetics of mangiferin, neomangiferin, timosaponin BII, anemarsaponin BIII and timosaponin AIII in rat plasma after oral administration of BZT and Zhimu extract (ZME). A sensitive, reliable and robust LC-MS/MS method to simultaneously determine steroid saponins and flavonoids in rat plasma was successfully validated. Significant differences (p < 0.05) were found in the pharmacokinetic parameters of timosaponin BII, anemarsaponin BIII and timosaponin AIII between BZT and ZME. It was surmised that formula compatibility could significantly influence the pharmacokinetics of BZT and our study is the first to study the administration of BZT based on pharmacokinetic studies.

Population Pharmacokinetics of Fentanyl in the Critically Ill

PubMed Central

Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E; Pandharipande, Pratik P; Heltsley, Rebecca; Ely, E Wesley; Stein, C Michael; Girard, Timothy D

2016-01-01

Objective To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design Prospective cohort study. Setting Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients Patients with acute respiratory failure and/or shock who received fentanyl during the first five days of their ICU stay. Measurements and Main Results We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to five days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance (CL), intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 (95% confidence interval: 32 to 39) L/hr, 55 (42 to 68) L/hr, 203 (140 to 266) L, and 523 (428 to 618) L, respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart disease were included. Conclusions In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID:26491862

Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol).

PubMed

Chan, Lingtak-Neander; Anderson, Gail D

2014-12-01

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

Pharmacokinetics of oral terbinafine in adult horses.

PubMed

Younkin, T J; Davis, E G; Kukanich, B

2017-08-01

The primary study objective was to compare the pharmacokinetics of p.o. terbinafine alone to p.o. terbinafine administered with p.o. cimetidine in healthy adult horses. The second objective was to assess the pharmacokinetics of terbinafine when administered per rectum in two different suspensions at 30 mg/kg to adult horses. Six healthy adult horses were included in this crossover study. Plasma terbinafine concentrations were quantified with liquid chromatography and mass spectrometry. The half-life (geometric mean) was 8.38 and 10.76 h, for p.o. alone and p.o. with cimetidine, respectively. The mean maximum plasma concentrations were 0.291 μg/mL at 1.54 h and 0.418 μg/mL at 1.28 h for p.o. alone and p.o. with cimetidine, respectively. Terbinafine with cimetidine had an average C MAX 44% higher and the relative F was 153% compared p.o. terbinafine alone, but was not statistically different (P > 0.05). Terbinafine was infrequently detected when administered per rectum in two different suspensions (water or olive oil). Minor adverse effects included oral irritation, fever, and colic. All resolved spontaneously. More pharmacokinetic studies are indicated assessing drug-drug interactions and using multiple dosing intervals to improve our knowledge of effective oral dosing, the potential for drug accumulation, and systemic adverse effect of terbinafine in horses. © 2016 John Wiley & Sons Ltd.

Pharmacokinetics of Cannabis in Cancer Cachexia-Anorexia Syndrome.

PubMed

Reuter, Stephanie E; Martin, Jennifer H

2016-07-01

Anorexia can affect up to 90 % of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose-concentration and concentration-response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population.

Changing Places: A Study of Chinese Students in the UK

ERIC Educational Resources Information Center

Gu, Qing; Maley, Alan

2008-01-01

This article explores the way tertiary level Chinese students in the UK adapt, in varying degrees, to their new learning and living environment. A questionnaire and interview study that includes both Chinese students and their British teachers attempts to ascertain key issues with a view to helping sojourning students adapt to their environment,…

Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

PubMed

Dansirikul, Chantaratsamon; Choi, Malcolm; Duffull, Stephen B

2005-06-01

This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

Effect of personality type on pharmacodynamics through changing pharmacokinetics.

PubMed

Xu, Feng

2007-01-01

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

UK health performance: findings of the Global Burden of Disease Study 2010.

PubMed

Murray, Christopher J L; Richards, Michael A; Newton, John N; Fenton, Kevin A; Anderson, H Ross; Atkinson, Charles; Bennett, Derrick; Bernabé, Eduardo; Blencowe, Hannah; Bourne, Rupert; Braithwaite, Tasanee; Brayne, Carol; Bruce, Nigel G; Brugha, Traolach S; Burney, Peter; Dherani, Mukesh; Dolk, Helen; Edmond, Karen; Ezzati, Majid; Flaxman, Abraham D; Fleming, Tom D; Freedman, Greg; Gunnell, David; Hay, Roderick J; Hutchings, Sally J; Ohno, Summer Lockett; Lozano, Rafael; Lyons, Ronan A; Marcenes, Wagner; Naghavi, Mohsen; Newton, Charles R; Pearce, Neil; Pope, Dan; Rushton, Lesley; Salomon, Joshua A; Shibuya, Kenji; Vos, Theo; Wang, Haidong; Williams, Hywel C; Woolf, Anthony D; Lopez, Alan D; Davis, Adrian

2013-03-23

The UK has had universal free health care and public health programmes for more than six decades. Several policy initiatives and structural reforms of the health system have been undertaken. Health expenditure has increased substantially since 1990, albeit from relatively low levels compared with other countries. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to examine the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010. We used results of GBD 2010 for 1990 and 2010 for the UK and 18 other comparator nations (the original 15 members of the European Union, Australia, Canada, Norway, and the USA; henceforth EU15+). We present analyses of trends and relative performance for mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 259 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to the UK. We assessed the UK's rank for age-standardised YLLs and DALYs for their leading causes compared with EU15+ in 1990 and 2010. We estimated 95% uncertainty intervals (UIs) for all measures. For both mortality and disability, overall health has improved substantially in absolute terms in the UK from 1990 to 2010. Life expectancy in the UK increased by 4·2 years (95% UI 4·2-4·3) from 1990 to 2010. However, the UK performed significantly worse than the EU15+ for age-standardised death rates, age-standardised YLL rates, and life expectancy in 1990, and its relative position had worsened by 2010. Although in most age groups, there have been reductions in age-specific mortality, for men aged 30-34 years, mortality rates have hardly changed (reduction of 3·7%, 95% UI 2·7-4·9). In terms of premature

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

PubMed

Sánchez Navarro, Amparo

2005-01-01

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

Morphine Pharmacokinetics in Children With Down Syndrome Following Cardiac Surgery.

PubMed

Goot, Benjamin H; Kaufman, Jon; Pan, Zhaoxing; Bourne, David W A; Hickey, Francis; Twite, Mark; Galinkin, Jeffrey; Christians, Uwe; Zuk, Jeannie; da Cruz, Eduardo M

2018-05-01

To assess if morphine pharmacokinetics are different in children with Down syndrome when compared with children without Down syndrome. Prospective single-center study including subjects with Down syndrome undergoing cardiac surgery (neonate to 18 yr old) matched by age and cardiac lesion with non-Down syndrome controls. Subjects were placed on a postoperative morphine infusion that was adjusted as clinically necessary, and blood was sampled to measure morphine and its metabolites concentrations. Morphine bolus dosing was used as needed, and total dose was tracked. Infusions were continued for 24 hours or until patients were extubated, whichever came first. Postinfusion, blood samples were continued for 24 hours for further evaluation of kinetics. If patients continued to require opioid, a nonmorphine alternative was used. Morphine concentrations were determined using a unique validated liquid chromatography tandem-mass spectrometry assay using dried blood spotting as opposed to large whole blood samples. Morphine concentration versus time data was modeled using population pharmacokinetics. A 16-bed cardiac ICU at an university-affiliated hospital. Forty-two patients (20 Down syndrome, 22 controls) were enrolled. None. The pharmacokinetics of morphine in pediatric patients with and without Down syndrome following cardiac surgery were analyzed. No significant difference was found in the patient characteristics or variables assessed including morphine total dose or time on infusion. Time mechanically ventilated was longer in children with Down syndrome, and regarding morphine pharmacokinetics, the covariates analyzed were age, weight, presence of Down syndrome, and gender. Only age was found to be significant. This study did not detect a significant difference in morphine pharmacokinetics between Down syndrome and non-Down syndrome children with congenital heart disease.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

PubMed

Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van't Klooster, Gerben

2015-08-01

Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

[Pharmacokinetical and clinical study of cefpirome in children].

PubMed

Kida, K; Morimoto, T; Matsuda, H; Murase, M

1991-02-01

This study describes the pharmacokinetic characteristics and clinical usefulness of cefpirome (CPR) in children. Mean half-lives of 20 mg/kg and 40 mg/kg of CPR injected intravenously in one shot were 1.18 and 1.34 hours, respectively, and their mean recovery rates into urine were 69.8 and 72.2%, respectively. Minimum inhibitory concentrations of CPR against Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli and Haemophilus influenzae were the same as or lower than those of ceftazidime. CPR was clinically effective in 14/15 of patients with bacterial infections; 8/9 of pneumonia, 2/2 of bronchitis, 1/1 of pharyngitis, 1/1 of tonsillitis, 1/1 of osteomyelitis, 1/1 of urinary tract infection. No clinically overt side effects of CPR were found, while an increase of eosinophils in blood was observed in 2 cases, and an increase of platelet in blood in 1 case and an elevation of serum GPT activity in 1 case were also observed. These findings indicate that CPR is useful for the treatment of bacterial infections in children.

The pharmacokinetics of xylazine hydrochloride: an interspecific study.

PubMed

Garcia-Villar, R; Toutain, P L; Alvinerie, M; Ruckebusch, Y

1981-06-01

The pharmacokinetic disposition of xylazine hydrochloride is described after both intravenous and intramuscular injection of a single dose, in four domestic species: horse, cattle, sheep and dog, by an original high performance liquid chromatographic technique. Remarkably small interspecific differences are reported. After intravenous administration, systemic half-life (t1/2 beta) ranged between 22 min (sheep) and 50 min (horse) while the distribution phase is transient with half-life (t1/2 alpha) ranging from 1.2 min (cattle) to 5.9 min (horse). The peak level of drug concentration in the plasma is reached after 12-14 min in all the species studied following intramuscular administration. Xylazine bioavailability, as measured by the ratios of the areas under the intravenous and intramuscular plasma concentration versus time curves, ranged from 52% to 90% in dog, 17% to 73% in sheep and 40% to 48% in horse. The low dosage in cattle did not permit calculation. Kinetic data are correlated with clinical data and the origins of interspecific differences are discussed.

Pharmacokinetic interplay of phase II metabolism and transport: a theoretical study.

PubMed

Wu, Baojian

2012-01-01

Understanding of the interdependence of cytochrome P450 enzymes and P-glycoprotein in disposition of drugs (also termed "transport-metabolism interplay") has been significantly advanced in recent years. However, whether such "interplay" exists between phase II metabolic enzymes and efflux transporters remains largely unknown. The objective of this article is to explore the role of efflux transporters (acting on the phase II metabolites) in disposition of the parent drug in Caco-2 cells, liver, and intestine via simulations utilizing a catenary model (for Caco-2 system) and physiologically based pharmacokinetic (PBPK) models (for the liver and intestine). In all three models, "transport-metabolism interplay" (i.e., inhibition of metabolite efflux decreases the metabolism) can be observed only when futile recycling (or deconjugation) occurred. Futile recycling appeared to bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof. Without futile recycling, metabolite formation was independent on its downstream process excretion, thus impact of metabolite excretion on its formation was impossible. Moreover, in liver PBPK model with futile recycling, impact of biliary metabolite excretion on the exposure of parent drug [(systemic (reservoir) area under the concentration-time curve (AUC(R1))] was limited; a complete inhibition of efflux resulted in AUC(R1) increases of less than 1-fold only. In intestine PBPK model with futile recycling, even though a complete inhibition of efflux could result in large elevations (e.g., 3.5-6.0-fold) in AUC(R1), an incomplete inhibition of efflux (e.g., with a residual activity of ≥ 20% metabolic clearance) saw negligible increases (<0.9-fold) in AUC(R1). In conclusion, this study presented mechanistic observations of pharmacokinetic interplay between phase II enzymes and efflux transporters. Those studying such "interplay" are encouraged to adequately consider potential consequences of

Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine.

PubMed

Bailey, David G; Dresser, George K; Urquhart, Brad L; Freeman, David J; Arnold, John Malcolm

2016-12-01

A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals. © American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Pharmacokinetic studies of the recombinant chicken interferon-α in broiler chickens.

PubMed

Zhao, Jun; Yu, Hai-Yang; Zhang, Jun-Ling; Wang, Xing-Man; Li, Jin-Pei; Hu, Tao; Hu, Yong; Wang, Ming-Li; Shen, Yong-Zhou; Xu, Jing-Dong; Han, Guo-Xiang; Chen, Jason

2017-02-14

In this study, 24 male and female broiler chickens at 30-day-old were divided into three groups with 8 animals in each group. The animals were administered with recombinant chicken interferon-α (rChIFN-α) at a dose of 1.0 × 10 6 IU/kg intravenously, intramuscularly or subcutaneously, respectively. Serum samples were collected at different time points post administration, and the titers of rChIFN-α in the blood were determined by cytopathic effect inhibition assay. The results showed that the pharmacokinetic characteristics of rChIFN-α by intramuscular injection and subcutaneous injection were fitted to one compartment open model, and the T max was 3.21 ± 0.79 hr and 3.95 ± 0.85 hr, respectively, and the elimination half-life (T 1/2 ) was 6.20 ± 2.77 hr and 5.03 ± 3.70 hr, respectively. In contrast, the pharmacokinetics of rChIFN-α via intravenous injection was in line with the open model of two-compartment and was eliminated in the first order, and the elimination half-life (T 1/2 ) was 4.61 ± 0.84 hr. In addition, compared with those in the intravenous group and the subcutaneous group, the bioavailability of rChIFN-α in the intramuscular group was 82.80%. In conclusion, rChIFN-α was rapidly absorbed and slowly eliminated after intramuscular administration of single dose of rChIFN-α aqueous formulations. Thus, rChIFN-α can be used as a commonly-used therapeutic agent.

Pharmacokinetic consequences of spaceflight

NASA Technical Reports Server (NTRS)

Putcha, L.; Cintron, N. M.

1991-01-01

Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

First plasma and tissue pharmacokinetic study of the YSNSG cyclopeptide, a new integrin antagonist, using microdialysis.

PubMed

Slimano, Florian; Djerada, Zoubir; Bouchene, Salim; Van Gulick, Laurence; Brassart-Pasco, Sylvie; Dukic, Sylvain

2017-07-15

The YSNSG peptide is a synthetic peptide targeting α v β 3 integrin. This peptide exhibits promising activity in vitro and in vivo against melanoma. To determine pharmacokinetic parameters and predictive active doses in the central nervous system (CNS) and subcutaneous tissue (SC), we conducted microdialysis coupled with pharmacokinetic modeling and Monte Carlo simulation. After a recovery period of surgical procedures, a microdialysis probe was inserted in the caudate and in subcutaneous tissue. Plasma samples and dialysates collected 5h after YSNSG intravenous administration (10mg/kg) were analyzed by UPLC-MS/MS. A nonlinear mixed-effect modeling approach implemented in Monolix® 2016R1 was performed. Model selection and evaluation were based on the usual diagnostic plot, precision and information criteria. The primary plasma and tissue pharmacokinetic parameters were comparable with those of other integrin antagonists, such as cilengitide or ATN-161. Tissue/plasma and brain/plasma area under the curve (AUC) ratio were 66.2±21.6% and 3.6±4.7%, respectively. Two models of 2-compartments with an additional microdialysis compartment, parameterized as rate constants (k for elimination, k12/k21 and k13/k31 for distribution) and volumes (central V1 and peripheral microdialysis compartment V3) with zero-order input were selected to describe the dialysate concentrations in CNS and SC. The inter-individual variability (IIV) was described by exponential terms, and residual variability was described by a combined additive and proportional error model. Individual AUC (plasma and tissues) values were derived for each animal using the Empirical-Bayes-Estimates of the individual parameters. The regimens needed to achieve an in vitro predetermined target concentration in tissues were studied by Monte Carlo simulations using Monolix® 2016R1. YSNSG pharmacokinetic parameters show promising results in terms of subcutaneous disposition. Further investigations into such

Interspecies Mixed-Effect Pharmacokinetic Modeling of Penicillin G in Cattle and Swine

PubMed Central

Li, Mengjie; Gehring, Ronette; Tell, Lisa; Baynes, Ronald; Huang, Qingbiao

2014-01-01

Extralabel drug use of penicillin G in food-producing animals may cause an excess of residues in tissue which will have the potential to damage human health. Of all the antibiotics, penicillin G may have the greatest potential for producing allergic responses to the consumer of food animal products. There are, however, no population pharmacokinetic studies of penicillin G for food animals. The objective of this study was to develop a population pharmacokinetic model to describe the time-concentration data profile of penicillin G across two species. Data were collected from previously published pharmacokinetic studies in which several formulations of penicillin G were administered to diverse populations of cattle and swine. Liver, kidney, and muscle residue data were also used in this study. Compartmental models with first-order absorption and elimination were fit to plasma and tissue concentrations using a nonlinear mixed-effect modeling approach. A 3-compartment model with extra tissue compartments was selected to describe the pharmacokinetics of penicillin G. Typical population parameter estimates (interindividual variability) were central volumes of distribution of 3.45 liters (12%) and 3.05 liters (8.8%) and central clearance of 105 liters/h (32%) and 16.9 liters/h (14%) for cattle and swine, respectively, with peripheral clearance of 24.8 liters/h (13%) and 9.65 liters/h (23%) for cattle and 13.7 liters/h (85%) and 0.52 liters/h (40%) for swine. Body weight and age were the covariates in the final pharmacokinetic models. This study established a robust model of penicillin for a large and diverse population of food-producing animals which could be applied to other antibiotics and species in future analyses. PMID:24867969

Simultaneous determination of leucine, isoleucine and valine in Beagle dog plasma by HPLC-MS/MS and its application to a pharmacokinetic study.

PubMed

Wang, Ting; Xie, Huiru; Chen, Xu; Jiang, Xuehua; Wang, Ling

2015-10-10

Leucine (Leu), isoleucine (Ile) and valine (Val) are three branched-chain amino acids (BCAAs), which have been widely used as dietary supplements for professional athletes and patients with liver failure or catabolic diseases. To date, no pharmacokinetic studies of BCAAs in vivo useful for the assessment of clinical effect following daily intake has been reported. Thus in this study, an HPLC-MS/MS method for simultaneous determination of Leu, Ile and Val in Beagle dog plasma using homoarginine as the internal standard was developed and validated in terms of specificity, linearity, precision, accuracy, and stability. This assay method was then applied to a pharmacokinetic study of BCAAs in dogs following oral administration of 0.25 g/kg and 0.50 g/kg BCAAs. The HPLC-MS/MS method was found to be sensitive and reproducible for quantification of BCAAs in dog plasma and successfully applied to the pharmacokinetic study. All these BCAAs were well absorbed with a substantial increase in the plasma concentration after a baseline modification. No statistical significance was identified in different gender group and no drug accumulation was observed following multiple doses. Copyright © 2015 Elsevier B.V. All rights reserved.

The pharmacokinetics of mianserin suppositories for rectal administration in dogs and healthy volunteers: a pilot study.

PubMed

Nawata, Shuichi; Kohyama, Noriko; Uchida, Naoki; Numazawa, Satoshi; Ohbayashi, Masayuki; Kobayashi, Yasuna; Iwata, Masanori; Nakajima, Takanori; Saito, Hiroshi; Izuka, Akira; Yamamoto, Toshinori

2016-01-01

We formulated mianserin suppositories for the treatment of delirium and evaluated their pharmacokinetics by measuring plasma drug concentrations in dogs and healthy human volunteers. Mianserin suppositories were prepared by a melting technique using Tetramide® tablets and Witepsol H-15 as the suppository base. Pharmacokinetics of this 30-mg mianserin preparation were evaluated in three beagle dogs and three healthy adult males, in line with ethics committee approval. Plasma mianserin levels were determined using gas chromatography-mass spectrometry. In dogs, the maximum plasma mianserin concentration (Cmax) was 1.3 ± 0.4 ng/mL, the time to Cmax (tmax) was 5.5 ± 4.3 h, and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) was 18.9 ± 1.9 h・ng/mL. In humans, the Cmax was 14.6 ± 6.3 ng/mL, the tmax was 8 h, and the AUC0-24 was 266 ± 103 h・ng/mL. The current study characterized the pharmacokinetics of mianserin suppositories in dogs and humans. As compared to oral administration, the suppositories produced a lower Cmax and a delayed tmax, although AUC0-24 values were comparable. It will be necessary to identify an appropriate dose that produces an adequate plasma mianserin concentration for effective and safe clinical use. UMIN000013853.

Enantioselective pharmacokinetics of sibutramine in rat.

PubMed

Noh, Keumhan; Bae, Kyoungjin; Min, Bokyoung; Kim, Eunyoung; Kwon, Kwang-il; Jeong, Taecheon; Kang, Wonku

2010-02-01

Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl-metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the C ( max ) and the AUC ( inf ) were 28 and 30 times higher than those of the R-isomer, respectively (p<0.001). In the urine, the concentrations of the R-isomers of hydroxylated DDS and hydroxylated and carbamoylglucuronized MDS and DDS appeared to be 11.3-, 5.1-, and 5.3-times the concentrations of the respective S-isomers. Thus, regardless of increased potency than the S-enantiomers, the R-enantiomers of the sibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats.

Pharmacokinetic Modeling of Perfluoroalkyl Acids in Rodents

EPA Science Inventory

Perfluorooctanoic acid (PFOA) has pharmacokinetic properties that appear consistent with a number of processes that are currently not well understood. Studies in mice exposed orally at lower doses (1 and 10 mg/kg) demonstrated blood, liver, and kidney concentration time courses ...

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

PubMed

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

2016-12-01

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

Pharmacokinetics of Intravenous Levofloxacin Administered at 750 Milligrams in Obese Adults ▿

PubMed Central

Cook, Aaron M.; Martin, Craig; Adams, Val R.; Morehead, R. Scott

2011-01-01

The physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing. PMID:21576432

Clinical Pharmacokinetics of Vemurafenib.

PubMed

Zhang, Weijiang; Heinzmann, Dominik; Grippo, Joseph F

2017-09-01

Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF V600 mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15-21 days and exposure at steady state is relatively constant. Population pharmacokinetic analysis identified a vemurafenib half-life of ≈57 h and elimination appears to be predominantly via the hepatic route. Pharmacokinetic parameters are generally consistent regardless of age, sex or race. No dose adjustments are necessary for patients with mild or moderate hepatic or renal impairment, but the effects of severe hepatic or renal impairment on vemurafenib pharmacokinetics are uncertain. Vemurafenib appears to be a substrate and inducer of cytochrome P450 (CYP) 3A4, a moderate inhibitor of CYP1A2 and both a substrate and inhibitor of the drug efflux transporters P-glycoprotein and breast cancer resistance protein. The relationship between plasma vemurafenib concentrations and response remains to be clarified.

PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT

EPA Science Inventory

A physiologically-based pharmacokinetic (PBPK) model was used to describe pharmacokinetics of permethrin and calibrated using experimental data on the concentration time-course of cis- and trans-permethrin in rat blood and brain tissues following oral administration...

Population pharmacokinetics of intravenous acetaminophen in Japanese patients undergoing elective surgery.

PubMed

Imaizumi, Tsuyoshi; Obara, Shinju; Mogami, Midori; Iseki, Yuzo; Hasegawa, Makiko; Murakawa, Masahiro

2017-06-01

Intravenous (i.v.) acetaminophen is administered during surgery for postoperative analgesia. However, little information is available on the pharmacokinetics of i.v. acetaminophen in Japanese patients undergoing surgery under general anesthesia. The study was approved by the Institutional Review Board and registered at UMIN-CTR (UMIN000013418). Patients scheduled to undergo elective surgery under general anesthesia were enrolled after obtaining written informed consent. During surgery, 1 g of i.v. acetaminophen was administered over 15, 60, or 120 min. Acetaminophen concentrations (15 or 16 samples per case) were measured at time points from 0-480 min after the start of administration (liquid chromatography-mass spectrometry/tandem mass spectrometry; limit of quantitation 0.1 μg/mL). The predictive performance of three published pharmacokinetic models was evaluated. Population pharmacokinetics were also analyzed using a nonlinear mixed-effect model based on the NONMEM program. Data from 12 patients who underwent endoscopic or lower limb procedures were analyzed (male/female = 7/5, median age 55 years, weight 63 kg). Anesthesia was maintained with remifentanil and propofol or sevoflurane. The pharmacokinetic model of i.v. acetaminophen reported by Würthwein et al. worked well. Using 185 datapoints, the pharmacokinetics of i.v. acetaminophen were described by a two-compartment model with weight as a covariate but not age, sex, or creatinine clearance. The median prediction error and median absolute prediction error of the final model were -1 and 10%, respectively. A population pharmacokinetic model of i.v. acetaminophen in Japanese patients was constructed, with performance within acceptable ranges.

Pharmacokinetic evaluation of avicularin using a model-based development approach.

PubMed

Buqui, Gabriela Amaral; Gouvea, Dayana Rubio; Sy, Sherwin K B; Voelkner, Alexander; Singh, Ravi S P; da Silva, Denise Brentan; Kimura, Elza; Derendorf, Hartmut; Lopes, Norberto Peporine; Diniz, Andrea

2015-03-01

The aim of this study was to use the pharmacokinetic information of avicularin in rats to project a dose for humans using allometric scaling. A highly sensitive and specific bioanalytical assay to determine avicularin concentrations in the plasma was developed and validated for UPLC-MS/MS. The plasma protein binding of avicularin in rat plasma determined by the ultrafiltration method was 64%. The pharmacokinetics of avicularin in nine rats was studied following an intravenous bolus administration of 1 mg/kg and was found to be best described by a two-compartment model using a nonlinear mixed effects modeling approach. The pharmacokinetic parameters were allometrically scaled by body weight and centered to the median rat weight of 0.23 kg, with the power coefficient fixed at 0.75 for clearance and 1 for volume parameters. Avicularin was rapidly eliminated from the systemic circulation within 1 h post-dose, and the avicularin pharmacokinetic was linear up to 5 mg/kg based on exposure comparison to literature data for a 5-mg/kg single dose in rats. Using allometric scaling and Monte Carlo simulation approaches, the rat doses of 1 and 5 mg/kg correspond to the human equivalent doses of 30 and 150 mg, respectively, to achieve comparable plasma avicularin concentrations in humans. Georg Thieme Verlag KG Stuttgart · New York.

The medline UK filter: development and validation of a geographic search filter to retrieve research about the UK from OVID medline.

PubMed

Ayiku, Lynda; Levay, Paul; Hudson, Tom; Craven, Jenny; Barrett, Elizabeth; Finnegan, Amy; Adams, Rachel

2017-07-13

A validated geographic search filter for the retrieval of research about the United Kingdom (UK) from bibliographic databases had not previously been published. To develop and validate a geographic search filter to retrieve research about the UK from OVID medline with high recall and precision. Three gold standard sets of references were generated using the relative recall method. The sets contained references to studies about the UK which had informed National Institute for Health and Care Excellence (NICE) guidance. The first and second sets were used to develop and refine the medline UK filter. The third set was used to validate the filter. Recall, precision and number-needed-to-read (NNR) were calculated using a case study. The validated medline UK filter demonstrated 87.6% relative recall against the third gold standard set. In the case study, the medline UK filter demonstrated 100% recall, 11.4% precision and a NNR of nine. A validated geographic search filter to retrieve research about the UK with high recall and precision has been developed. The medline UK filter can be applied to systematic literature searches in OVID medline for topics with a UK focus. © 2017 Crown copyright. Health Information and Libraries Journal © 2017 Health Libraries GroupThis article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.

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

PubMed

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

2017-06-14

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

Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies.

PubMed

Moss, Darren Michael; Marzolini, Catia; Rajoli, Rajith K R; Siccardi, Marco

2015-01-01

The pharmacokinetic properties of anti-infective drugs are a determinant part of treatment success. Pathogen replication is inhibited if adequate drug levels are achieved in target sites, whereas excessive drug concentrations linked to toxicity are to be avoided. Anti-infective distribution can be predicted by integrating in vitro drug properties and mathematical descriptions of human anatomy in physiologically based pharmacokinetic models. This method reduces the need for animal and human studies and is used increasingly in drug development and simulation of clinical scenario such as, for instance, drug-drug interactions, dose optimization, novel formulations and pharmacokinetics in special populations. We have assessed the relevance of physiologically based pharmacokinetic modeling in the anti-infective research field, giving an overview of mechanisms involved in model design and have suggested strategies for future applications of physiologically based pharmacokinetic models. Physiologically based pharmacokinetic modeling provides a powerful tool in anti-infective optimization, and there is now no doubt that both industry and regulatory bodies have recognized the importance of this technology. It should be acknowledged, however, that major challenges remain to be addressed and that information detailing disease group physiology and anti-infective pharmacodynamics is required if a personalized medicine approach is to be achieved.

Stereoselective pharmacokinetic study of rhynchophylline and isorhynchophylline epimers in rat plasma by liquid chromatography-tandem mass spectrometry.

PubMed

Wang, Xin; Zheng, Mei; Liu, Jia; Qiao, Zhou; Liu, Wenyuan; Feng, Feng

2017-06-01

1. In this study, the stereoselective pharmacokinetics of rhynchophylline (RIN) and isorhynchophylline (IRN) in rat plasma were investigated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 2. A rapid, robust and sensitive LC-MS/MS method for simultaneous quantification of RIN and IRN in rat plasma was established and validated. Chromatographic separation was performed on a Poroshell 120 EC-C 18 column under a gradient elution with methanol and water containing 0.01% ammonia as mobile phase. Calibration curve was linear over a concentration range of 1-2000 ng/mL for both epimers. 3. After intravenous administration, there was no apparent difference in pharmacokinetic parameters between two epimers. However, after oral administration, RIN showed remarkable higher plasma exposure than IRN. The bioavailability, C max and AUC 0- t of RIN were about 9.2-fold, 6.4-fold and 9.1-fold higher than those of IRN at 10 mg/kg, and 7.8-fold, 4.3-fold and 7.7-fold at 20 mg/kg, respectively. Additionally, with dosage enhanced from 10 mg/kg to 20 mg/kg, the plasma concentrations of RIN or IRN increased significantly and the bioavailability enhanced about three times. 4. In conclusion, the results of this work demonstrated for the first time that the pharmacokinetics of RIN and IRN have stereoselectivity.

A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan.

PubMed

Midgley, R S; Kerr, D J; Flaherty, K T; Stevenson, J P; Pratap, S E; Koch, K M; Smith, D A; Versola, M; Fleming, R A; Ward, C; O'Dwyer, P J; Middleton, M R

2007-12-01

This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination. Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination. The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease. The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Prophylactic ranitidine treatment in critically ill children – a population pharmacokinetic study

PubMed Central

Hawwa, Ahmed F; Westwood, Paul M; Collier, Paul S; Millership, Jeffrey S; Yakkundi, Shirish; Thurley, Gillian; Shields, Mike D; Nunn, Anthony J; Halliday, Henry L; McElnay, James C

2013-01-01

Aims To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (−12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h−1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h−1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary. PMID:23016949

Reconstructing Exposures from Biomarkers using Exposure-Pharmacokinetic Modeling - A Case Study with Carbaryl

EPA Science Inventory

Sources of uncertainty involved in exposure reconstruction for a short half-life chemical, carbaryl, were characterized using the Cumulative and Aggregate Risk Evaluation System (CARES), an exposure model, and a human physiologically based pharmacokinetic (PBPK) model. CARES was...

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

PubMed Central

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

2016-01-01

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

Pharmacokinetic parameters explain the therapeutic activity of antimicrobial agents in a silkworm infection model.

PubMed

Paudel, Atmika; Panthee, Suresh; Urai, Makoto; Hamamoto, Hiroshi; Ohwada, Tomohiko; Sekimizu, Kazuhisa

2018-01-25

Poor pharmacokinetic parameters are a major reason for the lack of therapeutic activity of some drug candidates. Determining the pharmacokinetic parameters of drug candidates at an early stage of development requires an inexpensive animal model with few associated ethical issues. In this study, we used the silkworm infection model to perform structure-activity relationship studies of an antimicrobial agent, GPI0039, a novel nitrofuran dichloro-benzyl ester, and successfully identified compound 5, a nitrothiophene dichloro-benzyl ester, as a potent antimicrobial agent with superior therapeutic activity in the silkworm infection model. Further, we compared the pharmacokinetic parameters of compound 5 with a nitrothiophene benzyl ester lacking chlorine, compound 7, that exerted similar antimicrobial activity but had less therapeutic activity in silkworms, and examined the metabolism of these antimicrobial agents in human liver fractions in vitro. Compound 5 had appropriate pharmacokinetic parameters, such as an adequate half-life, slow clearance, large area under the curve, low volume of distribution, and long mean residence time, compared with compound 7, and was slowly metabolized by human liver fractions. These findings suggest that the therapeutic effectiveness of an antimicrobial agent in the silkworms reflects appropriate pharmacokinetic properties.

State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development.

PubMed

Yellepeddi, Venkata; Rower, Joseph; Liu, Xiaoxi; Kumar, Shaun; Rashid, Jahidur; Sherwin, Catherine M T

2018-05-18

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and

PHARMACOKINETICS OF PIROXICAM IN CRANES (FAMILY GRUIDAE).

PubMed

Keiper, Naomi L; Cox, Sherry K; Doss, Grayson A; Elsmo, Betsy; Franzen-Klein, Dana; Hartup, Barry K

2017-09-01

To investigate the pharmacokinetics of the nonsteroidal anti-inflammatory drug (NSAID) piroxicam in cranes, three brolgas (Antigone rubicunda) were administered piroxicam as a single oral dose at 0.5 mg/kg and 1.0 mg/kg during separate trials. Serial blood samples were collected for quantification of piroxicam in plasma. Piroxicam was readily absorbed at both dosages, and no adverse effects were observed. Plasma concentrations peaked at 3.67 hr with a concentration of 4.00 μg/ml for the lower dosage, and at 0.83 hr at 8.77 μg/ml for the higher dosage. Piroxicam may exhibit linear kinetics and dose proportionality in brolgas, but will require further study. Mean peak plasma concentrations in brolgas were comparable to concentrations demonstrated to be analgesic in humans. To the authors' knowledge, this study represents the first pharmacokinetic investigation of piroxicam in an avian species.

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy Greyhound dogs

PubMed Central

KuKanich, Butch; Allen, Philip

2014-01-01

The purpose of this study was to compare the pharmacokinetics of two highly protein bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy Greyhound dogs (3 males and 3 females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL/min/kg) was faster than buprenorphine (10.3 mL/min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including: octanol:water partition coefficient and pKa the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. PMID:24684621

Rats and rabbits as pharmacokinetic screening tools for long acting intramuscular depots: case study with paliperidone palmitate suspension.

PubMed

Patel, Harilal; Patel, Prakash; Modi, Nirav; Patel, Pinakin; Wagh, Yogesh; George, Alex; Desai, Nirmal; Srinivas, Nuggehally R

2018-05-08

Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance. The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work. Sparse sampling composite study was used in rats, (Wistar/Sprague-Dawley (SD; n = 10)) and a serial blood sampling study design was used in rabbits (n = 4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5 mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis. Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (T max ) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0-28) days) were 18,597, 21,865 and 18,120 ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8-10 days). Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s).

Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women.

PubMed

Tran, Anna H; Best, Brookie M; Stek, Alice; Wang, Jiajia; Capparelli, Edmund V; Burchett, Sandra K; Kreitchmann, Regis; Rungruengthanakit, Kittipong; George, Kathleen; Cressey, Tim R; Chakhtoura, Nahida; Smith, Elizabeth; Shapiro, David E; Mirochnick, Mark

2016-07-01

Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL. Median (range) AUC0-24 were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37-225, n = 17), 56 (<10-181, n = 30), and 81 (<10-299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3-0.8, n = 21). Delivery HIV-1 RNA was ≤50 copies per milliliter in 70% and ≤400 copies per milliliter in 90% of women. Cmin were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10-93) vs 63 (15-200) ng/mL (P = 0.0001). Cmin was below the protein binding-adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10

Evaluation of the reproducibility of a protocol for the pharmacokinetic study of breast tumors by dynamic magnetic resonance imaging.

PubMed

Etxano, J; García-Lallana Valbuena, A; Antón Ibáñez, I; Elizalde, A; Pina, L; García-Foncillas, J; Boni, V

2015-01-01

To evaluate the reproducibility of a protocol for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the pharmacokinetic study of breast tumors. We carried out this prospective study from October 2009 through December 2009. We studied 12 patients with stage ii-iii invasive breast cancer without prior treatment. Our center's research ethics committee approved the study. The 12 patients underwent on two consecutive days DCE-MRI with a high temporal resolution protocol (21 acquisitions/minute). The data obtained in an ROI traced around the largest diameter of the tumor (ROI 1) and in another ROI traced around the area of the lesion's highest K(trans) intensity (ROI 2) were analyzed separately. We used parametric and nonparametric statistical tests to study the reproducibility and concordance of the principal pharmacokinetic variables (K(trans), Kep, Ve and AUC90). The correlations were very high (r>.80; P<.01) for all the variables for ROI 1 and high (r=.70-.80; P<.01) for all the variables for ROI 2, with the exception of Ve both in ROI 1 (r=.44; P=.07) and in ROI 2 (r=.13; P=.235). There were no statistically significant differences between the two studies in the values obtained for K(trans), Kep and AUC90 (P>.05 for each), but there was a statistically significant difference between the two studies in the values obtained for Ve in ROI 2 (P=.008). The high temporal resolution protocol for DCE-MRI used at out center is very reproducible for the principal pharmacokinetic constants of breast. Copyright © 2012 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Pharmacokinetics of cefpirome during the posttraumatic systemic inflammatory response syndrome.

PubMed

Jacolot, A; Incagnoli, P; Edouard, A R; Tod, M; Petitjean, O; Samii, K; Mimoz, O

1999-05-01

To determine the pharmacokinetic parameters of cefpirome, a new so-called fourth-generation cephalosporin, in previously healthy trauma patients with posttraumatic systemic inflammatory response syndrome (SIRS) and to compare them to parameters obtained in matched, healthy volunteers. A prospective study. 12-bed surgical intensive care unit in a university hospital. 9 severe [Injury Severity Score, median (range) 29 (16-50)] trauma patients on mechanical ventilation with proven or suspected cefpirome-susceptible nosocomial infection, with no renal or hepatic failure, and healthy volunteers matched for age (+/- 5 years), sex, and body surface area (+/- 10%) were enrolled. All were men. Cefpirome (2 g twice daily) was continuously infused over a 0.5 h period alone or concomitantly with ciprofloxacin (400 mg over 1 h, twice daily). Antibiotic concentrations in plasma were measured by high-performance liquid chromatography; their pharmacokinetic parameters were evaluated at 12 time points after the first drug administration using a noncompartmental model. Cefpirome pharmacokinetic parameters for the two groups were similar despite a wider variation for trauma patients. Specifically, the median (range) time during which the cefpirome concentration in plasma remained over 4 mg/l (corresponding to the French lower cutoff determining cefpirome susceptibility) was 9.5 (7- > 12) and 9 (8-12) h for trauma patients and healthy volunteers, respectively. In the group of five patients receiving combined antibiotic therapy, the interindividual variability of pharmacokinetics was wider for ciprofloxacin than for cefpirome. No major pharmacokinetic modification was noted when cefpirome was given to trauma patients with posttraumatic SIRS without significant organ failure, indicating that no dosage adjustment seems required in this population. However, larger studies including determination of antibiotic levels in tissues are warranted to confirm these results.

Nonlinear pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine in mice.

PubMed

Shen, Hong-Wu; Jiang, Xi-Ling; Yu, Ai-Ming

2011-07-01

5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses.

Usefulness and pharmacokinetic study of oral terbinafine for hyperkeratotic-type tinea pedis.

PubMed

Kikuchi, Izumi; Tanuma, Hiroyuki; Morimoto, Kensuke; Kawana, Seiji

2008-11-01

To study and establish an optimal administration method of oral antifungal, terbinafine (TBF), for hyperkeratotic-type tinea pedis from the pharmacokinetic point of view, 20 patients with hyperkeratotic-type tinea pedis were given TBF 125 mg once daily for 4 weeks and observed over time for improvement of dermatological symptoms and mycological efficacy. Targeting five of the patients, TBF concentration in the stratum corneum was measured using the LC-MS/MS method. TBF was detected in the stratum corneum of the sole 1 week after beginning the treatment in some cases and reached its peak 1 week after the completion of the treatment with a concentration of 247.8 ng g(-1), which was approximately more than 50 times higher than its minimal inhibitory concentration against dermatophytes. TBF was not detected at 8 weeks post-treatment, although its concentration was 50.73 ng g(-1) at 6 weeks post-treatment. All cases were subjected to analysis for final total efficacy, general safety and usefulness. Its effectiveness rate (effective + markedly effective) was 95% (19/20) with no adverse reactions, including abnormal changes in the laboratory test values, in any patients. From the above, it is noted that TBF showed excellent efficacy and safety for refractory hyperkeratotic-type tinea pedis, and also it was considered as a useful drug to treat cutaneous mycosis, including hyperkeratotic-type tinea pedis, from the pharmacokinetic point of view.

In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation.

PubMed

Hao, Wei-Hua; Wang, Jong-Jing; Hsueh, Shu-Ping; Hsu, Pei-Jing; Chang, Li-Chien; Hsu, Chang-Shan; Hsu, Kuang-Yang

2013-02-01

The chemotherapy agent gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. In order to assess the pharmacokinetics and antitumor activity of D07001-F4, a new self-microemulsifying oral drug delivery system preparation of gemcitabine, this study was performed to compare the effect of D07001-F4 with administered gemcitabine in vitro and in vivo. D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice. Antitumor activity was evaluated by comparing the effect of D07001-F4 and gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and gemcitabine in two xenograft tumor models in mice. In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34%. D07001-F4 was effective against several cancer types, was metabolized more slowly than gemcitabine hydrochloride, and exhibited enhanced oral bioavailability.

A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions

PubMed Central

Li, R; Barton, HA; Maurer, TS

2015-01-01

Liver cirrhosis is a disease characterized by the loss of functional liver mass. Physiologically based pharmacokinetic (PBPK) modeling was applied to interpret and predict how the interplay among physiological changes in cirrhosis affects pharmacokinetics. However, previous PBPK models under cirrhotic conditions were developed for permeable cytochrome P450 substrates and do not directly apply to substrates of liver transporters. This study characterizes a PBPK model for liver transporter substrates in relation to the severity of liver cirrhosis. A published PBPK model structure for liver transporter substrates under healthy conditions and the physiological changes for cirrhosis are combined to simulate pharmacokinetics of liver transporter substrates in patients with mild and moderate cirrhosis. The simulated pharmacokinetics under liver cirrhosis reasonably approximate observations. This analysis includes meta-analysis to obtain system-dependent parameters in cirrhosis patients and a top-down approach to improve understanding of the effect of cirrhosis on transporter-mediated drug disposition under cirrhotic conditions. PMID:26225262

A randomised cross-over pharmacokinetic bioavailability study of synthetic versus kiwifruit-derived vitamin C.

PubMed

Carr, Anitra C; Bozonet, Stephanie M; Vissers, Margreet C M

2013-11-11

Kiwifruit are a rich source of vitamin C and also contain numerous phytochemicals, such as flavonoids, which may influence the bioavailability of kiwifruit-derived vitamin C. The aim of this study was to compare the relative bioavailability of synthetic versus kiwifruit-derived vitamin C using a randomised cross-over pharmacokinetic study design. Nine non-smoking males (aged 18-35 years) received either a chewable tablet (200 mg vitamin C) or the equivalent dose from gold kiwifruit (Actinidia chinensis var. Sungold). Fasting blood and urine were collected half hourly to hourly over the eight hours following intervention. The ascorbate content of the plasma and urine was determined using HPLC with electrochemical detection. Plasma ascorbate levels increased from 0.5 h after the intervention (P = 0.008). No significant differences in the plasma time-concentration curves were observed between the two interventions (P = 0.645). An estimate of the total increase in plasma ascorbate indicated complete uptake of the ingested vitamin C tablet and kiwifruit-derived vitamin C. There was an increase in urinary ascorbate excretion, relative to urinary creatinine, from two hours post intervention (P < 0.001). There was also a significant difference between the two interventions, with enhanced ascorbate excretion observed in the kiwifruit group (P = 0.016). Urinary excretion was calculated as ~40% and ~50% of the ingested dose from the vitamin C tablet and kiwifruit arms, respectively. Overall, our pharmacokinetic study has shown comparable relative bioavailability of kiwifruit-derived vitamin C and synthetic vitamin C.

Optical Coherence Tomography in the UK Biobank Study - Rapid Automated Analysis of Retinal Thickness for Large Population-Based Studies.

PubMed

Keane, Pearse A; Grossi, Carlota M; Foster, Paul J; Yang, Qi; Reisman, Charles A; Chan, Kinpui; Peto, Tunde; Thomas, Dhanes; Patel, Praveen J

2016-01-01

To describe an approach to the use of optical coherence tomography (OCT) imaging in large, population-based studies, including methods for OCT image acquisition, storage, and the remote, rapid, automated analysis of retinal thickness. In UK Biobank, OCT images were acquired between 2009 and 2010 using a commercially available "spectral domain" OCT device (3D OCT-1000, Topcon). Images were obtained using a raster scan protocol, 6 mm x 6 mm in area, and consisting of 128 B-scans. OCT image sets were stored on UK Biobank servers in a central repository, adjacent to high performance computers. Rapid, automated analysis of retinal thickness was performed using custom image segmentation software developed by the Topcon Advanced Biomedical Imaging Laboratory (TABIL). This software employs dual-scale gradient information to allow for automated segmentation of nine intraretinal boundaries in a rapid fashion. 67,321 participants (134,642 eyes) in UK Biobank underwent OCT imaging of both eyes as part of the ocular module. 134,611 images were successfully processed with 31 images failing segmentation analysis due to corrupted OCT files or withdrawal of subject consent for UKBB study participation. Average time taken to call up an image from the database and complete segmentation analysis was approximately 120 seconds per data set per login, and analysis of the entire dataset was completed in approximately 28 days. We report an approach to the rapid, automated measurement of retinal thickness from nearly 140,000 OCT image sets from the UK Biobank. In the near future, these measurements will be publically available for utilization by researchers around the world, and thus for correlation with the wealth of other data collected in UK Biobank. The automated analysis approaches we describe may be of utility for future large population-based epidemiological studies, clinical trials, and screening programs that employ OCT imaging.

Comparative bioavailability and pharmacokinetics of two oral formulations of flurbiprofen: a single-dose, randomized, open-label, two-period, crossover study in Pakistani subjects.

PubMed

Qayyum, Aisha; Najmi, Muzammil Hasan; Abbas, Mateen

2013-11-01

Comparative bioavailability studies are conducted to establish the bioequivalence of generic formulation with that of branded reference formulation, providing confidence to clinicians to use these products interchangeably. This study was carried out to compare a locally manufactured formulation of flurbiprofen with that of a branded product. Twenty two healthy male adults received a single dose of flurbiprofen (100mg) either generic or branded product according to randomization scheme on each of 2 periods. Blood samples were collected and plasma flurbiprofen concentration was determined by a validated HPLC method. Pharmacokinetic parameters like AUC(0-t), AUC(0-oo), Cmax, Tmax, t½, Vd and clearance were determined. The 90% CI for the ratio of geometric means of test to reference product's pharmacokinetic variables was calculated. Pharmacokinetic parameters for two formulations were comparable. Ratio of means of AUC(0-24), AUC(0-oo) and Cmax for test to reference products and 90% CI for these ratios were within the acceptable range. The p-values calculated by TOST were much less than the specified value (p-0.05). ANOVA gave p-values which were more than the specified value (p-0.05) for sequence, subject, period and formulation. Test formulation of flurbiprofen (tablet Flurso) was found to meet the criteria for bioequivalence to branded product (tablet Ansaid) based on pharmacokinetic parameters.

Histone Deacetylase Inhibitor MS-275 Exhibits Poor Brain Penetration: Pharmacokinetic Studies of [11C]MS-275 using Positron Emission Tomography

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

Hooker, J.M.; Hooker, J.M.; Kim, S.W.

2009-10-01

MS-275 (entinostat) is a histone deacetylase (HDAC) inhibitor currently in clinical trials for the treatment of several types of cancer. Recent reports have noted that MS-275 can cross the blood-brain barrier (BBB) and cause region-specific changes in rodent brain histone acetylation. To characterize the pharmacokinetics and distribution of MS-275 in the brain using positron emission tomography (PET), we labeled the carbamate carbon of MS-275 with carbon-11. Using PET, we determined that [{sup 11}C]MS-275 has low uptake in brain tissue when administered intravenously to nonhuman primates. In rodent studies, we observed that pharmacokinetics and brain accumulation of [{sup 11}C]MS-275 were notmore » changed by the coadministration of large doses of unlabeled MS-275. These results, which both highlight the poor brain penetration of MS-275, clearly suggest its limitation as a therapeutic agent for the central nervous system (CNS). Moreover, our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for HDAC inhibitors. These data are important not only for the development of new compounds for peripheral cancer treatment (where CNS exclusion is often advantageous) but also for the treatment of neurological disorders (where CNS penetration is critical).« less

Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.

PubMed

Law, Francis C P; Yao, Meicun; Bi, Hui-Chang; Lam, Stephen

2017-06-01

Although green tea ( Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products.

Research priorities for respiratory nursing: a UK-wide Delphi study.

PubMed

Kelly, Carol Ann; Kirkcaldy, Andrew J; Pilkington, Melissa; Hodson, Matthew; Welch, Lindsay; Yorke, Janelle; Knighting, Katherine

2018-04-01

Respiratory nurses make a significant contribution to the delivery of respiratory healthcare, but there is a dearth of nurse-led, practice-focused, published research. Using a modified three-round Delphi, this study sought to identify research priorities for respiratory nursing to inform a national research strategy. Study information and the survey link were sent electronically to members of UK professional respiratory organisations. Round 1 had 78 items across 16 topics, informed by a systematic literature review. Respondents suggested additional items which were content analysed to inform Round 2. Respondents rated all items and ranked the topics in all rounds. To ensure rigour, rounds had an explicit focus with pre-determined criteria for consensus (70%). In total, 363 responses were received across Rounds 1, 2 and 3 (n=183, 95 and 85, respectively). The top five research priorities were: 1) "Patient understanding of asthma control"; 2) "The clinical and cost-effectiveness of respiratory nurse interventions"; 3) "The impact of nurse-led clinics on patient care"; 4) "Inhaler technique"; and 5) two topics jointly scored: "Prevention of exacerbations" and "Symptom management". With potential international significance, this is the first UK study to identify research priorities for respiratory nursing, providing direction for those planning or undertaking research.

Research priorities for respiratory nursing: a UK-wide Delphi study

PubMed Central

Pilkington, Melissa; Hodson, Matthew; Welch, Lindsay; Yorke, Janelle

2018-01-01

Respiratory nurses make a significant contribution to the delivery of respiratory healthcare, but there is a dearth of nurse-led, practice-focused, published research. Using a modified three-round Delphi, this study sought to identify research priorities for respiratory nursing to inform a national research strategy. Study information and the survey link were sent electronically to members of UK professional respiratory organisations. Round 1 had 78 items across 16 topics, informed by a systematic literature review. Respondents suggested additional items which were content analysed to inform Round 2. Respondents rated all items and ranked the topics in all rounds. To ensure rigour, rounds had an explicit focus with pre-determined criteria for consensus (70%). In total, 363 responses were received across Rounds 1, 2 and 3 (n=183, 95 and 85, respectively). The top five research priorities were: 1) “Patient understanding of asthma control”; 2) “The clinical and cost-effectiveness of respiratory nurse interventions”; 3) “The impact of nurse-led clinics on patient care”; 4) “Inhaler technique”; and 5) two topics jointly scored: “Prevention of exacerbations” and “Symptom management”. With potential international significance, this is the first UK study to identify research priorities for respiratory nursing, providing direction for those planning or undertaking research. PMID:29692999

Dapoxetine has no pharmacokinetic or cognitive interactions with ethanol in healthy male volunteers.

PubMed

Modi, Nishit B; Dresser, Mark; Desai, Dhaval; Edgar, Christopher; Wesnes, Keith

2007-03-01

Dapoxetine is being investigated for the treatment of premature ejaculation. This study evaluated the potential pharmacokinetic and cognitive interactions of dapoxetine 60 mg with ethanol 0.5 g/kg in a single-center, double-blind, randomized, placebo-controlled crossover study in healthy adult male participants (n = 24). Dapoxetine was rapidly absorbed and eliminated; peak concentrations were noted 1.47 hours after administration and decreased with an alpha half-life of 1.33 hours and a terminal half-life of 15.6 hours. Pharmacokinetic parameters (C(max), AUC(infinity), t((1/2)), and t(max)) of dapoxetine were not altered with concurrent ethanol consumption. Furthermore, coadministration of dapoxetine did not affect the pharmacokinetics of ethanol or potentiate the cognitive and subjective effects of ethanol.

PET Studies of d-Methamphetamine Pharmacokinetics in Primates: Comparison with l-Methamphetamine and (—)-Cocaine

PubMed Central

Fowler, Joanna S.; Kroll, Carsten; Ferrieri, Richard; Alexoff, David; Logan, Jean; Dewey, Stephen L.; Schiffer, Wynne; Schlyer, David; Carter, Pauline; King, Payton; Shea, Colleen; Xu, Youwen; Muench, Lisa; Benveniste, Helene; Vaska, Paul; Volkow, Nora D.

2009-01-01

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (—)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. Methods d- and l-methamphetamine and (—)-cocaine were labeled with 11C via alkylation of the norprecursors with 11C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2–3 h apart to determine the distribution and kinetics of 11C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. 11C-d-Methamphetamine pharmacokinetics were compared with 11C-l-methamphetamine and 11C-(—)-cocaine in both brain and peripheral organs in the same animal. Results 11C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. 11C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of 11C-d-methamphetamine and 11C-(—)-cocaine showed that 11C-d-methamphetamine peaked later in the brain than did 11C-(—)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys

Truth-Telling in the UK Jewish Studies Classroom for Orthodox Educators

ERIC Educational Resources Information Center

Burman, Chaim

2017-01-01

UK Orthodox Jewish educators face a number of ethical dilemmas surrounding truth-telling in the classroom. While they must comply with government legislation and high standards of professional conduct, they may also wish their practice to be informed by halachic considerations. This theoretical study explores the potential tensions that may arise…

[Bemetil pharmacokinetics in an experiment on rats].

PubMed

Boĭko, S S; Bobkov, Iu G; Zherdev, V P; Dvorianinov, A A

1987-01-01

Pharmacokinetics of bemetil (2-ethyl-mercaptobenzimidazole), a representative of the group of actoprotectors, was studied at intravenous and intragastric administration during the experiment on rats by using gas-liquid chromatography. It was found that at intragastric administration the drug rapidly appeared in the systemic circulation, reached the maximal concentration in one hour; the character of bemetil elimination from the blood was biexponential at both routes of administration. The two-compartment model was used for calculation of the main pharmacokinetic constants and bioavailability. The analysis of the experimental findings on urinary excretion of bemetil made it possible to conclude that little amount of the drug (0.56%) is excreted in the urine in the unchanged form; most amount of bemetil is excreted in the form of metabolites and in the bound state.

Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension.

PubMed

Kodati, Devender; Kotakonda, Harish Kaushik; Yellu, Narsimhareddy

2017-08-01

Olmesartan medoxomil is an orally given angiotensin II receptor antagonist indicated for the treatment of hypertension. The aim of the study was to establish a population pharmacokinetic model for olmesartan, the active metabolite of olmesartan medoxomil, in Indian hypertensive patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of olmesartan. The population pharmacokinetic model for olmesartan was developed using Phoenix NLME 1.3 with a non-linear mixed-effect model. Bootstrap and visual predictive check were used simultaneously to validate the final population pharmacokinetic models. The covariates included age, sex, body surface area (BSA), bodyweight, height, creatinine clearance (CL CR ) as an index of renal function and liver parameters as indices of hepatic function. A total of 205 olmesartan plasma sample concentrations from 69 patients with hypertension were collected in this study. The pharmacokinetic data of olmesartan was well described by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and V/F of olmesartan in the patients were 0.31565 L/h and 44.5162 L, respectively. Analysis of covariates showed that age and CL CR were factors influencing the clearance of olmesartan and the volume of distribution of olmesartan was dependent on age and BSA. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of olmesartan in Indian patients with hypertension.

[Study on the pharmacokinetics Oxytropis falcate total flavonoids ointment in rats].

PubMed

Li, Wei-Dong; Chen, Zhi-Peng; Qu, Min-Ming; Liu, Dan; Xiao, Yan-Yu; Cai, Bao-Chang

2011-09-01

To study the pharmacokinetics of Oxytropis falcate total flavonoids ointment after transdermal administration in rats. The content of 2',4'-dihydroxychalcone (TFC) in plasma was determined by high performance liquid chromatography. The concentration was determined at various time and the data was processed by 3P97. TFC behaved as a one-compartment and a two-compartment model after transdermal administration of total Oxytropis falcate total flavonoids ointment and solution, respectively. And the C(max) of ointment was improved about 3 times compared with that of the solution. The results show that the ointment possesses sustained release property and significantly prolong the degradation half life of TFC. The ointment is benefit to improve the analgesic and anti-inflammatory activity after transdermal administration.

Effects of mesocaval shunt on the pharmacokinetics of metronidazole in young rats.

PubMed

Guillé, Beatriz E Perez; Alvarez, Fernando Villegas; Toledo López, Alejandra R; Bravo-Luna, Miguel A Jiménez; Soriano-Rosales, Rosa E; Lares-Asseff, Ismael; Arrellin, Gerardo; Guillé, Maria G Pérez

2005-01-01

Prophylactic and therapeutic management of portosystemic encephalopathies is based on protein restriction in the diet, and the use of lactulose and antibiotics such as metronidazole. These actions intend to reduce the main source of intestinal ammonia production and release into the systemic circulation. The aim of this study was to evaluate the medium-term effects of mesocaval shunt on the pharmacokinetics of metronidazole in rats with healthy livers. Male Lewis rats were divided into two groups. The first group was subjected to mesocaval shunt (MCS) and the other employed as a control. The following tests were carried out in both groups: metronidazole pharmacokinetics, determination of ALT, AST, albumin, urea and ammonium, liver weight and histomorphology. A loss in body and liver weight was registered in rats subjected to MCS. AST levels also increased compared to controls. Significant differences in almost all pharmacokinetic parameters were detected between MCS and control rats, especially in Kel, AUC and Cmax. Modifications in metronidazole pharmacokinetics and liver weight changes without microstructural modification secondary to MCS were found. We suggest that individual drug-monitoring and pharmacokinetic analysis must be carried out in metronidazole medicated patients with modifications in portal circulation with or with out macro or micro liver structural alterations.

Computer-Assisted Learning in UK Engineering Degree Programmes: Lessons Learned from an Extensive Case Study Programme

ERIC Educational Resources Information Center

Rothberg, S. J.; Lamb, F. M.; Willis, L.

2006-01-01

This paper gives a synopsis of an extensive programme of case studies on real uses of computer-assisted learning (CAL) materials within UK engineering degree programmes. The programme was conducted between 2000 and 2003 and followed a questionnaire-based survey looking at CAL use in the UK and in Australia. The synopsis reveals a number of key…

Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study)

PubMed Central

Niven, Robert M; Saralaya, Dinesh; Chaudhuri, Rekha; Masoli, Matthew; Clifton, Ian; Mansur, Adel H; Hacking, Victoria; McLain-Smith, Susan; Menzies-Gow, Andrew

2016-01-01

Objective To describe the impact of omalizumab on asthma management in patients treated as part of normal clinical practice in the UK National Health Service (NHS). Design A non-interventional, mixed methodology study, combining retrospective and prospective data collection for 12 months pre-omalizumab and post-omalizumab initiation, respectively. Setting Data were collected in 22 UK NHS centres, including specialist centres and district general hospitals in the UK. Participants 258 adult patients (aged ≥16 years; 65% women) with severe persistent allergic asthma treated with omalizumab were recruited, of whom 218 (84.5%) completed the study. Primary and secondary outcome measures The primary outcome measure was change in mean daily dose of oral corticosteroids (OCS) between the 12-month pre-omalizumab and post-omalizumab initiation periods. A priori secondary outcome measures included response to treatment, changes in OCS dosing, asthma exacerbations, lung function, employment/education, patient-reported outcomes and hospital resource utilisation. Results The response rate to omalizumab at 16 weeks was 82.4%. Comparing pre-omalizumab and post-omalizumab periods, the mean (95% CIs) daily dose of OCS decreased by 1.61 (−2.41 to −0.80) mg/patient/day (p<0.001) and hospital exacerbations decreased by 0.97 (−1.19 to −0.75) exacerbations/patient (p<0.001). Compared with baseline, lung function, assessed by percentage of forced expiratory volume in 1 s, improved by 4.5 (2.7 to 6.3)% at 16 weeks (p<0.001; maintained at 12 months) and patient quality of life (Asthma Quality of Life Questionnaire) improved by 1.38 (1.18 to 1.58) points at 16 weeks (p<0.001, maintained at 12 months). 21/162 patients with complete employment data gained employment and 6 patients lost employment in the 12-month post-omalizumab period. The mean number of A&E visits, inpatient hospitalisations, outpatient visits (excluding for omalizumab) and number of bed days

Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles.

PubMed

Lea-Henry, Tom N; Carland, Jane E; Stocker, Sophie L; Sevastos, Jacob; Roberts, Darren M

2018-06-22

Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review. Copyright © 2018 by the American Society of Nephrology.

Population Pharmacokinetics of Phenobarbital in Infants with Neonatal Encephalopathy treated with Therapeutic Hypothermia

PubMed Central

Shellhaas, Renée A.; Ng, Chee M; Dillon, Christina H.; Barks, John D.E.; Bhatt-Mehta, Varsha

2013-01-01

Objective Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy (HIE) are treated with therapeutic hypothermia (TH) and about 40% have clinical seizures. Little is known about pharmacokinetics of phenobarbital in infants with HIE who undergo TH. The objective of this study was to determine the effect of TH on phenobarbital pharmacokinetics, taking into account maturational changes. Setting Level 3 neonatal intensive care unit. Patients Infants with HIE and suspected seizures, all treated with phenobarbital. Some of these infant also received treatment with TH. Interventions None. Design A retrospective cohort study of 39 infants with HIE treated with phenobarbital (20 were treated with TH and 19 were not). Measurements and main results Data were collected on phenobarbital plasma concentrations on 39 subjects with HIE with or without TH. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance (CL) of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. TH did not influence the pharmacokinetic parameters of phenobarbital. Conclusions TH does not influence the CL of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for initial treatment of seizures in neonates with HIE treated with TH. PMID:23254984

Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia.

PubMed

Shellhaas, Renée A; Ng, Chee M; Dillon, Christina H; Barks, John D E; Bhatt-Mehta, Varsha

2013-02-01

Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes. Level 3 neonatal ICU. Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia. None. A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not). Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital. Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

A cooperative study of gate entry designs: Welbeck Colliery (UK) and Jim Walter Resources (USA)

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

Hendon, G.; Carr, F.; Lewis, A.

1995-11-01

Longwall developments in the UK have historically consisted of single entry gate roads. Adjacent developments were separated from existing pales by large barrier pillars (designed of sufficient width to get away from the longwall abutments of the previous panel) or by small barriers driven in the shadow, or de-stressed zone, of the previous panel. Some 2nd panel tailgates were also driven skin to skin leaving no coal barrier between the newly driven entry and the heavily supported existing gateroad. With the development and wide acceptance of fully bolted entries and the pressure to reduce production costs, alternatives to single entrymore » drivage, particularly yield pillar developments, were examined. Through the Rock Mechanics Branch of british Coal, a cooperative study was begun with Jim Walter Resources, Inc., USA, (JWR) to look at the yield pillar alternative in detail. This study was to determine the feasibility of utilizing yield pillars in the UK and to determine, through monitoring, the possibility of reducing stable pillar widths at JWR. The study has included extensive monitoring of the yield-stable-yield pillar system at JWR No. 7 Mine and an underground trial of a two entry yield pillar test area at Welbeck Colliery in the UK. This paper describes results from the JWR study and the subsequent results of the first advancing yield pillar development in the UK at Welbeck Colliery.« less

A Population Pharmacokinetic and Pharmacodynamic Analysis of Abemaciclib in a Phase I Clinical Trial in Cancer Patients.

PubMed

Tate, Sonya C; Sykes, Amanda K; Kulanthaivel, Palaniappan; Chan, Edward M; Turner, P Kellie; Cronier, Damien M

2018-03-01

Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels. A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model. The pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (F rel ) adequately described the pharmacokinetics of abemaciclib. Serum albumin and alkaline phosphatase were the only significant covariates identified in the model, the inclusion of which reduced inter-individual variability in F rel by 10.3 percentage points. By combining the clinical popPK model with the previously developed pre-clinical pharmacokinetic/pharmacodynamic model, the extent of target engagement in skin in cancer patients was successfully predicted. The proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight. NCT01394016 (ClinicalTrials.gov).

Effect of silibinin on the pharmacokinetics of nitrendipine in rabbits.

PubMed

Voruganti, Swathi; Yamsani, Shravan Kumar; Yamsani, Madhusudan Rao

2014-12-01

Silibinin, a major constituent of silymarin, is widely used for its hepatoprotective effects. This study investigated the effect of silibinin on the pharmacokinetics of oral nitrendipine in rabbits. In first set of experiment, male New Zealand rabbits were pretreated with silibinin (50 mg/kg, PO) for 7 days and on last day nitrendipine (10 mg/kg, PO) was administered. In second set, both silibinin and nitrendipine were coadministered to examine acute effect of silibinin on nitrendipine pharmacokinetics. The plasma concentration of nitrendipine was estimated by high performance liquid chromatography and different pharmacokinetic parameters were calculated using WinNonlin(®) software. Coadministration of silibinin had no significant effect on pharmacokinetics of nitrendipine when compared to control group. However, a 1.89-1.57-fold increase in area under the concentration-time curve and peak plasma concentration (C max), respectively, of nitrendipine was observed in silibinin pretreated group. The mean C max was 0.034 ± 0.005 μg/mL (nitrendipine alone) and 0.054 ± 0.006 μg/mL (nitrendipine after pretreatment with silibinin). The time to reach C max, elimination rate constant and elimination half-life of nitrendipine were not significantly different among control and silibinin treated groups. This study demonstrates that silibinin increase plasma concentration of nitrendipine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing nitrendipine to the patients already taking silymarin.

Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates

PubMed Central

Dostalek, Miroslav; Prueksaritanont, Thomayant; Kelley, Robert F.

2017-01-01

ABSTRACT Pharmacokinetic studies play an important role in all stages of drug discovery and development. Recent advancements in the tools for discovery and optimization of therapeutic proteins have created an abundance of candidates that may fulfill target product profile criteria. Implementing a set of in silico, small scale in vitro and in vivo tools can help to identify a clinical lead molecule with promising properties at the early stages of drug discovery, thus reducing the labor and cost in advancing multiple candidates toward clinical development. In this review, we describe tools that should be considered during drug discovery, and discuss approaches that could be included in the pharmacokinetic screening part of the lead candidate generation process to de-risk unexpected pharmacokinetic behaviors of Fc-based therapeutic proteins, with an emphasis on monoclonal antibodies. PMID:28463063

Determination and pharmacokinetic study of pirfenidone in rat plasma by UPLC-MS/MS.

PubMed

Sun, Wei; Jiang, Zhe-li; Zhou, Lei; Chen, Rui-min; Wang, Zhe; Li, Wan-shu; Jiang, Shuo-min; Hu, Guo-xin; Chen, Rui-jie

2015-02-15

A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of pirfenidone in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.0 min and the elution of pirfenidone was at 1.39 min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring (MRM) mode using the respective transitions m/z 186.2→92.1 for pirfenidone and m/z 237.1→194.2 for carbamazepine (IS), respectively. The calibration curve was linear over the range of 5-2000 ng/mL with a lower limit of quantitation (LLOQ) of 5 ng/mL. Mean recovery of pirfenidone in plasma was in the range of 80.4-84.3%. Intra-day and inter-day precision were both <12.1%. This method was successfully applied in pharmacokinetic study after oral administration of 10.0mg/kg pirfenidone in rats. Copyright © 2015 Elsevier B.V. All rights reserved.

Vascular input function correction of inflow enhancement for improved pharmacokinetic modeling of liver DCE-MRI.

PubMed

Ning, Jia; Schubert, Tilman; Johnson, Kevin M; Roldán-Alzate, Alejandro; Chen, Huijun; Yuan, Chun; Reeder, Scott B

2018-06-01

To propose a simple method to correct vascular input function (VIF) due to inflow effects and to test whether the proposed method can provide more accurate VIFs for improved pharmacokinetic modeling. A spoiled gradient echo sequence-based inflow quantification and contrast agent concentration correction method was proposed. Simulations were conducted to illustrate improvement in the accuracy of VIF estimation and pharmacokinetic fitting. Animal studies with dynamic contrast-enhanced MR scans were conducted before, 1 week after, and 2 weeks after portal vein embolization (PVE) was performed in the left portal circulation of pigs. The proposed method was applied to correct the VIFs for model fitting. Pharmacokinetic parameters fitted using corrected and uncorrected VIFs were compared between different lobes and visits. Simulation results demonstrated that the proposed method can improve accuracy of VIF estimation and pharmacokinetic fitting. In animal study results, pharmacokinetic fitting using corrected VIFs demonstrated changes in perfusion consistent with changes expected after PVE, whereas the perfusion estimates derived by uncorrected VIFs showed no significant changes. The proposed correction method improves accuracy of VIFs and therefore provides more precise pharmacokinetic fitting. This method may be promising in improving the reliability of perfusion quantification. Magn Reson Med 79:3093-3102, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Pharmacokinetic Drug Interactions with Panax ginseng.

PubMed

Ramanathan, Meenakshi R; Penzak, Scott R

2017-08-01

Panax ginseng is widely used as an adaptogen throughout the world. The major active constituents of P. ginseng are ginsenosides. Most naturally occurring ginsenosides are deglycosylated by colonic bacteria to intestinal metabolites. Ginsenosides along with these metabolites are widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng. Numerous preclinical studies have assessed the influence of various ginseng components on cytochrome P450 (CYP), glucuronidation, and drug transport activity. Results from these investigations have been largely inconclusive due to the use of different ginseng products and variations in methodology between studies. Drug interaction studies in humans have been conflicting and have largely yielded negative results or results that suggest only a weak interaction. One study using a midazolam probe found weak CYP3A induction and another using a fexofenadine probe found weak P-gp inhibition. Despite several case reports indicating a drug interaction between warfarin and P. ginseng, pharmacokinetic studies involving these agents in combination have failed to find significant pharmacokinetic or pharmacodynamic interactions. To this end, drug interactions involving P. ginseng appear to be rare; however, close clinical monitoring is still suggested for patients taking warfarin or CYP3A or P-gp substrates with narrow therapeutic indices.

A population pharmacokinetic analysis of the influence of nutritional status of digoxin in hospitalized Korean patients.

PubMed

Choi, Soo An; Yun, Hwi-yeol; Lee, Eun Sook; Shin, Wan Gyoon

2014-03-01

Safe and effective use of digoxin in hospitalized populations requires information about the drug's pharmacokinetics and the influence of various factors on drug disposition. However, no attempts have been made to link an individual's digoxin requirements with nutritional status. The main goal of this study was to estimate the population pharmacokinetics of digoxin and to identify the nutritional status that explains pharmacokinetic variability in hospitalized Korean patients. Routine therapeutic drug-monitoring data from 106 patients who received oral digoxin at Seoul National University Bundang Hospital were retrospectively collected. The pharmacokinetics of digoxin were analyzed with a 1-compartment, open-label pharmacokinetic model by using a nonlinear mixed-effects modeling tool (NONMEM) and a multiple trough screening approach. The effect of demographic characteristics and biochemical and nutritional indices were explored. Estimates generated by using NONMEM indicated that the CL/F of digoxin was influenced by renal function, serum potassium, age, and percentage of ideal body weight (PIBW). These influences could be modeled by following the equation CL/F (L/h) = 1.36 × (creatinine clearance/50)(1.580) × K(0.835) × 0.055 × (age/65) × (PIBW/100)(0.403). The interindividual %CV for CL/F was 34.3%, and the residual variability (SD) between observed and predicted concentrations was 0.225 μg/L. The median estimates from a bootstrap procedure were comparable and within 5% of the estimates from NONMEM. Correlation analysis with the validation group showed a linear correlation between observed and predicted values. The use of this model in routine therapeutic drug monitoring requires that certain conditions be met which are consistent with the conditions of the subpopulations in the present study. Therefore, further studies are needed to clarify the effects of nutritional status on digoxin pharmacokinetics. The present study established important sources of

The pharmacokinetics of intraosseous atropine in hypovolemic swine.

PubMed

Yost, Jonathan; Baldwin, Phillip; Bellenger, Sarah; Bradshaw, Freida; Causapin, Edna; Demotica, Richelle; Livingston, Michael; Lee, Cynthia; Gegel, Brian; Burgert, James; Claessens, Adam; Johnson, Don; Loughren, Michael

2015-01-01

Compare the pharmacokinetics of atropine administered via the intravenous (IV), intramuscular (IM), and intraosseous (IO) routes in a normovolemic and hypovolemic swine model. Prospective, between subjects, experimental study. Vivarium. Yorkshire-cross swine (N = 36). Atropine was administered via IV, IM, or IO routes to normovolemic and hypovolemic swine. Blood samples were drawn at regular intervals after atropine administration and analyzed for plasma atropine concentration. Pharmacokinetic parameters were obtained from modeling the plasma concentrations. Pharmacokinetic parameters, maximum concentration (Cmax) and time to maximum concentration (Tmax). The IV and IO groups in both the normovolemic and hypovolemic models reached peak plasma concentration immediately and had a very rapid distribution phase with no apparent absorption phase for the IO groups. Peak plasma concentration and time to reach peak concentration were both significantly lower for the IM groups. There was a significant increase in absorption time with IM administration in the hypovolemic model compared to the normovolemic model. The IO route is an effective method of administering atropine and is comparable to the IV route even under conditions of significant hemorrhage. Therapeutic levels of atropine may be delayed and possibly difficult to obtain via IM injection in the presence of hypovolemic shock.

Simultaneous determination of multiple angiotensin type 1 receptor antagonists and its application to high-throughput pharmacokinetic study

NASA Astrophysics Data System (ADS)

Zhu, Xiaoyan; Sun, Jianguo; Hao, Haiping; Wang, Guangji; Hu, Xiaoling; Lv, Hua; Gu, Shenghua; Wu, Xiaoming; Xu, Jinyi

2008-05-01

A rapid and sensitive high performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) detection was developed for the simultaneous determination of multiple angiotensin type 1 receptor antagonists (AT1RAs) WX472, WX581, 1b and telmisartan in rat plasma for the purpose of high-throughout pharmacokinetic screening. The method was operated under selected reaction monitoring (SRM) mode in the positive ion mode. The analytes and the internal standard (pitavastatin) were extracted from 100 [mu]L rat plasma under acidic conditions by liquid-liquid extraction with ethyl acetate. The analytes and internal standard were baseline separated on a Gemini analytical column (3 [mu]m, 150 mm × 2.0 mm) with the adoption of a gradient elution using acetonitrile and 0.05% aqueous formic acid. The standard curves were linear in the concentration ranges of 4.5-900 ng/mL for WX472, 5-1000 ng/mL for WX581 and 0.5-100 ng/mL for 1b and telmisartan. Intra- and inter-batch precisions (R.S.D.%) were all within 15% and the method assessed a quite good accuracy (R.E.%). Recoveries were found to be >65% for all the compounds and no obvious matrix effects were found. This method has been successfully applied to the high-throughput pharmacokinetic screening study for both cassette dosing and cassette analysis of four compounds to rats. Significant drug-drug interactions were observed after cassette dosing. The study suggested that cassette analysis of pooled samples would be a better choice for the high-throughput pharmacokinetic screening of angiotensin type 1 receptor antagonists.

The experience of international nursing students studying for a PhD in the U.K: A qualitative study.

PubMed

Evans, Catrin; Stevenson, Keith

2011-06-13

Educating nurses to doctoral level is an important means of developing nursing capacity globally. There is an international shortage of doctoral nursing programmes, hence many nurses seek their doctorates overseas. The UK is a key provider of doctoral education for international nursing students, however, very little is known about international doctoral nursing students' learning experiences during their doctoral study. This paper reports on a national study that sought to investigate the learning expectations and experiences of overseas doctoral nursing students in the UK. Semi-structured qualitative interviews were conducted in 2008/09 with 17 international doctoral nursing students representing 9 different countries from 6 different UK universities. Data were analysed thematically. All 17 interviewees were enrolled on 'traditional' 3 year PhD programmes and the majority (15/17) planned to work in higher education institutions back in their home country upon graduation. Studying for a UK PhD involved a number of significant transitions, including adjusting to a new country/culture, to new pedagogical approaches and, in some cases, to learning in a second language. Many students had expected a more structured programme of study, with a stronger emphasis on professional nursing issues as well as research - akin to the professional doctorate. Students did not always feel well integrated into their department's wider research environment, and wanted more opportunities to network with their UK peers. A good supervision relationship was perceived as the most critical element of support in a doctoral programme, but good relationships were sometimes difficult to attain due to differences in student/supervisor expectations and in approaches to supervision. The PhD was perceived as a difficult and stressful journey, but those nearing the end reflected positively on it as a life changing experience in which they had developed key professional and personal skills. Doctoral

The experience of international nursing students studying for a PhD in the U.K: A qualitative study

PubMed Central

2011-01-01

Background Educating nurses to doctoral level is an important means of developing nursing capacity globally. There is an international shortage of doctoral nursing programmes, hence many nurses seek their doctorates overseas. The UK is a key provider of doctoral education for international nursing students, however, very little is known about international doctoral nursing students' learning experiences during their doctoral study. This paper reports on a national study that sought to investigate the learning expectations and experiences of overseas doctoral nursing students in the UK. Methods Semi-structured qualitative interviews were conducted in 2008/09 with 17 international doctoral nursing students representing 9 different countries from 6 different UK universities. Data were analysed thematically. All 17 interviewees were enrolled on 'traditional' 3 year PhD programmes and the majority (15/17) planned to work in higher education institutions back in their home country upon graduation. Results Studying for a UK PhD involved a number of significant transitions, including adjusting to a new country/culture, to new pedagogical approaches and, in some cases, to learning in a second language. Many students had expected a more structured programme of study, with a stronger emphasis on professional nursing issues as well as research - akin to the professional doctorate. Students did not always feel well integrated into their department's wider research environment, and wanted more opportunities to network with their UK peers. A good supervision relationship was perceived as the most critical element of support in a doctoral programme, but good relationships were sometimes difficult to attain due to differences in student/supervisor expectations and in approaches to supervision. The PhD was perceived as a difficult and stressful journey, but those nearing the end reflected positively on it as a life changing experience in which they had developed key professional and

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI‐1 study

PubMed Central

Ring, Arne; Morris, Tom; Wozniak, Marcin; Sullo, Nikol; Dott, William; Verheyden, Veerle; Kumar, Tracy; Brunskill, Nigel; Vaja, Rakesh

2016-01-01

Aims Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. Methods We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. Results Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, C max 189.4 ng ml−1 and t 1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. Conclusions Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery. PMID:27779776

Omeprazole does not change the oral bioavailability or pharmacokinetics of vinpocetine in rats.

PubMed

Sozański, Tomasz; Magdalan, Jan; Trocha, Małgorzata; Szumny, Antoni; Merwid-Ląd, Anna; Słupski, Wojciech; Karaźniewicz-Łada, Marta; Kiełbowicz, Grzegorz; Ksiądzyna, Dorota; Szeląg, Adam

2011-01-01

Previous studies proved that food strongly enhanced the bioavailability of vinpocetine. Food may change the pharmacokinetics of a drug by affecting various factors, including gastrointestinal pH. However, the influence of proton pump inhibitor-induced pH alterations on vinpocetine pharmacokinetics is not known. The aim was to evaluate the influence of omeprazole on the pharmacokinetics of oral vinpocetine. One group of male Wistar rats received single oral doses of vinpocetine (2 mg/kg - regimen V). In the second group, omeprazole (10 mg/kg) was administered intraperitoneally for 5 days before vinpocetine administration (regimen OV). For analysis of vinpocetine pharmacokinetics, blood samples were obtained before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h after vinpocetine administration. Vinpocetine concentrations were measured by high performance liquid chromatography (HPLC). The mean values of AUC(0-t), AUC(0-inf) and C(max) in regimen V were very similar to respective values in regimen OV. The mean T(max) in both regimens was estimated for 1.5 h. There were no statistically significant differences between both regimens. In conclusion, omeprazole did not affect the pharmacokinetic profile of vinpocetine.

Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study.

PubMed

Flexman, Alana M; Wong, Harvey; Riggs, K Wayne; Shih, Tina; Garcia, Paul A; Vacas, Susana; Talke, Pekka O

2014-05-01

Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications. Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach. A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations. This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.

PubMed

Cheung, Tommy T; Salem, Ahmed Hamed; Menon, Rajeev M; Munasinghe, Wijith P; Bueno, Orlando F; Agarwal, Suresh K

2018-05-01

Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD C max , AUC inf , and terminal half-life were 1.0 ± 0.32 μg/mL, 12.6 ± 5.4 μg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax C max and AUC inf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open-label study in Chinese subjects with R/R CLL. © 2017, The American College of Clinical Pharmacology.

EVALUATION OF ORAL AND INTRAVENOUS ROUTE PHARMACOKINETICS, PLASMA PROTEIN BINDING AND UTERINE TISSUE DOSE METRICS OF BPA: A PHYSIOLOGICALLY BASED PHARMACOKINETIC APPROACH

EPA Science Inventory

Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastics and epoxy resins, both of which are used in food contact applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed t...

EVALUATION OF ORAL AND INTRAVENOUS ROUTE PHARMACOKINETICS, PLASMA PROTEIN BINDING AND UTERINE TISSUE DOSE METRICS OF BPA: A PHYSIOLOGICALLY BASED PHARMACOKINETIC APPROACH

EPA Science Inventory

Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastics and epoxy resins, both of which are used in food contact applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed ...

Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations.

PubMed

Ayoub, Bassam M; Mowaka, Shereen; Elzanfaly, Eman S; Ashoush, Nermeen; Elmazar, Mohamed M; Mousa, Shaker A

2017-05-31

The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were C max , T max , t 1/2 , elimination rate constant, AUC 0-t and AUC 0-inf . The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25-600 ng mL -1 ) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies.

An Assessment of Pharmacokinetics and Antioxidant Activity of Free Silymarin Flavonolignans in Healthy Volunteers: A Dose Escalation Study

PubMed Central

Zhu, Hao-Jie; Brinda, Bryan J.; Chavin, Kenneth D.; Bernstein, Hilary J.; Patrick, Kennerly S.

2013-01-01

Milk thistle (Silybum marianum) extracts, one of the most widely used dietary supplements, contain a mixture of six major flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin) and other components. However, the pharmacokinetics of the free individual flavonolignans have been only partially investigated in humans. Furthermore, antioxidant effects of the extract, which may underlie the basis of many therapeutic effects, have not been thoroughly assessed. The present study evaluated the pharmacokinetics of the six major flavonolignans in healthy volunteers receiving single doses of either one (175 mg), two (350 mg), or three (525 mg) milk thistle capsule(s) on three separate study visits. Additionally, the steady-state pharmacokinetic parameters were determined after the subjects were administered one capsule three times daily for 28 consecutive days. Our results demonstrated that all six flavonolignans were rapidly absorbed and eliminated. In order of abundance, the exposure to free flavonolignans was greatest for silybin A followed by silybin B, isosilybin B, isosilybin A, silychristin, and silydianin. The systemic exposure to these compounds appeared linear and dose proportional. The disposition of flavonolignans was stereoselective, as evidenced by the apparent clearance of silybin B, which was significantly greater than silybin A, whereas the apparent clearance of isosilybin B was significantly lower than isosilybin A. The concentrations of urinary 8-epi-prostaglandin F2α, a commonly used biomarker of oxidative status in humans, were considerably decreased in study subjects after a 28-day exposure to the extract (1.3 ± 0.9 versus 0.8 ± 0.9 ng/mg creatinine) but failed to reach statistical significance (P = 0.076). PMID:23835761

Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis.

PubMed

Jones, Aksana K; Freise, Kevin J; Agarwal, Suresh K; Humerickhouse, Rod A; Wong, Shekman L; Salem, Ahmed Hamed

2016-09-01

Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26 h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30-1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact.

Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics.

PubMed

Shan, Ning; Perry, Miranda L; Weyna, David R; Zaworotko, Michael J

2014-09-01

Pharmaceutical cocrystallization has emerged in the past decade as a new strategy to enhance the clinical performance of orally administered drugs. A pharmaceutical cocrystal is a multi-component crystalline material in which the active pharmaceutical ingredient is in a stoichiometric ratio with a second compound that is generally a solid under ambient conditions. The resulting cocrystal exhibits different solid-state thermodynamics, leading to changes in physicochemical properties that offer the potential to significantly modify drug pharmacokinetics. The impact of cocrystallization upon drug pharmacokinetics has not yet been well delineated. Herein, we compile previously published data to address two salient questions: what effect does cocrystallization impart upon physicochemical properties of a drug substance and to what degree can those effects impact its pharmacokinetics. Cocrystals can impact various aspects of drug pharmacokinetics, including, but not limited to, drug absorption. The diversity of solid forms offered through cocrystallization can facilitate drastic changes in solubility and pharmacokinetics. Therefore, it is unsurprising that cocrystal screening is now a routine step in early-stage drug development. With the increasing recognition of pharmaceutical cocrystals from clinical, regulatory and legal perspectives, the systematic commercialization of cocrystal containing drug products is just a matter of time.

Communicating geohazard information for emergency responders, a case study from the UK.

NASA Astrophysics Data System (ADS)

Banks, Vanessa; Cooper, Anthony

2016-04-01

SSS11.4/ESSI4.6/HS11.39/NH9.13 Communication of uncertain information in earth sciences: data, models and visualization Communicating geohazard information for emergency responders, a case study from the UK. Cooper, A. H.1, Banks, V.J.1, Cowup, P.2, Curness, J.3, Davis, R.4, Dawson, L3. and Gazzard, L.4 1 British Geological Survey, Keyworth, NG12 5GG, UK 2 London Fire Brigade, 169 Union Street, London, SE1 0LL, UK 3.Coventry University, Priory Street, Coventry, CV1 5FB, UK 4.Avon Fire and Rescue, Temple Back, Bristol, BS1 6EU, UK. In February 2013 a sinkhole opened beneath a Florida Home resulting in the loss of a life and demolition of the affected home. The resulting void was in the order of 15 m deep. Neighbouring homes also had to be demolished. Television footage of this unfortunate incident resonated with an Assistant Commissioner of the London Fire Brigade who questioned whether or not such a feature would be recognised in the UK and if so, how the emergency response would be managed. Stemming from this, the British Geological Survey was invited to work with the Chief Fire Officers Association Urban Search and Rescue working group on geohazards. The aim of this group was to develop national tactical operational guidance on geohazards that would form the basis for regional guidance and training. The project was addressed collaboratively providing opportunities for two students from the Coventry University Disaster Management course, that were on placements with Avon Fire and Rescue, to work with the BGS to develop the guidance. Key to the success of the project was an iterative approach to knowledge exchange with respect to firstly, the characterization of the geohazards, and the processes and uncertainties associated with them and secondly, with respect to emergency responders' needs and priorities. Effective communication was achieved through challenging and rationalising the geoscience language for the end user and through a series of customised

A study of HIV positive undocumented African migrants' access to health services in the UK.

PubMed

Whyte, James; Whyte, Maria D; Hires, Kimberly

2015-01-01

Newly immigrated persons, whatever their origin, tend to fall in the lower socioeconomic levels. In fact, failure of an asylum application renders one destitute in a large proportion of cases, often resulting in a profound lack of access to basic necessities. With over a third of HIV positive failed asylum seekers reporting no income, and the remainder reporting highly limited resources, poverty is a reality for the vast majority. The purpose of the study was to determine the basic social processes that guide HIV positive undocumented migrant's efforts to gain health services in the UK. The study used the Grounded Theory Approach. Theoretical saturation occurred after 16 participants were included in the study. The data included reflections of the prominent factors related to the establishment of a safe and productive life and the ability of individuals to remain within the UK. The data reflected heavily upon the ability of migrants to enter the medical care system during their asylum period, and on an emerging pattern of service denial after loss on immigration appeal. The findings of this study are notable in that they have demonstrated sequence of events along a timeline related to the interaction between the asylum process and access to health-related services. The results reflect that African migrants maintain a degree of formal access to health services during the period that they possess legal access to services and informal access after the failure of their asylum claim. The purpose of this paper is to examine the basic social processes that characterize efforts to gain access to health services among HIV positive undocumented African migrants to the UK. The most recent estimates indicate that there are a total of 618,000 migrants who lack legal status within the UK. Other studies have placed the number of undocumented migrants within the UK in the range of 525,000-950,000. More than 442,000 are thought to dwell in the London metropolitan area. Even in

Pharmacokinetics of ranitidine in preterm and term neonates with gastroesophageal reflux.

PubMed

Asseff, Ismael Lares; Gaucin, Graciela Benitez; Olguín, Hugo Juárez; Nájera, Jose Antonio Godinez; López, Alejandra Toledo; Guillé, Gabriela Pérez; Torres, Fausto Zamura

2016-07-13

The aim of this study was to determine the effect of gestational age on pharmacokinetics of ranitidine in newborns with gastroesophageal reflux. A prospective, descriptive and pharmacokinetic study was carried out in 30 pre-term and 20 full-term babies. 3 mg/kg of ranitidine was administered intravenously to all the babies and at 0.25, 0.5, 1, 2, 4, and 8 h following the administration, samples of blood were drawn to assess ranitidine levels using high performance liquid chromatographic technique. Pharmacokinetics of ranitidine had a bi-exponential behavior with a half-life elimination of (t1/2el) 2.79 h, area under curve (AUC) of 1688 ng/mL, volume of distribution (Vd) of 1.44 L/kg, and clearance (Cl) of 5.9 L/kg/h. The median plasmatic concentration in pre-terms was 1113 ng/mL and 280 ng/mL in full-terms. Vd, t1/2 and Cl presented high values in preterm although the correlation of Cl with glomerular filtration in term newborns was better. Plasma levels of ranitidine depend on the gestational age of the newborns. However, the possible relationship between after-birth age and pharmacokinetics of the neonates as their internal organs get matured without minding their gestational background.

Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study.

PubMed

Sousa, Joana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

2017-11-01

To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection. Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used. Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points. The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.

Pharmacokinetics of escin Ia in rats after intravenous administration.

PubMed

Wu, Xiu-Jun; Cui, Xiang-Yong; Tian, Lian-tian; Gao, Feng; Guan, Xin; Gu, Jing-Kai

2014-10-28

Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration. Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany). After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t₁/₂ was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5-2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia. The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5-2.0 mg

Comparative pharmacokinetics study of orientin in rat plasma by UHPLC-MS/MS after intravenous administration of single orientin and Trollius chinensis Bunge extract.

PubMed

Zhao, Nan; Sun, Qi; Song, Yang; Wang, Lin; Zhang, Tingjian; Meng, Fanhao

2018-04-01

Orientin showed a broad array of biological activities, and it is the major bioactive compound in the Trollius chinensis Bunge. The aim of this study was to investigate the comparative pharmacokinetics of orientin after intravenous administration of single orientin and T. chinensis Bunge extract. Sample preparation involved a simple one-step deproteinization procedure with acetonitrile. Chromatographic separation was achieved on a Waters BEH C 18 column with a mobile phase consisting of acetonitrile and water containing 0.1% formic acid in an isocratic elution way. The detection was accomplished in multiple reaction monitoring mode with positive electrospray ionization. The pharmacokinetic properties of orientin were compared after intravenous administrations of pure orientin and T. chinensis Bunge extract to rats with approximately the same dosage of 10 mg/kg. The results of the study indicate that the pharmacokinetics of orientin in rat plasma show significant differences between two groups. This is useful for the clinical uses of therapeutic dosing of orientin and T. chinensis Bunge. Copyright © 2017 John Wiley & Sons, Ltd.

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs.

PubMed

KuKanich, B; Allen, P

2014-12-01

The purpose of this study was to compare the pharmacokinetics of two highly protein-bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol-water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. © 2014 John Wiley & Sons Ltd.

Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants.

PubMed

Lee, Sun Ku; Xing, Jun; Catlett, Ian M; Adamczyk, Robert; Griffies, Amber; Liu, Ang; Murthy, Bindu; Nowak, Miroslawa

2017-06-01

BMS-986142 is an oral, small-molecule reversible inhibitor of Bruton's tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5-900 mg) or multiple doses (25-350 mg, once daily for 14 days). In a drug-drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concentration-dependent inhibition of CD69 expression was observed following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.

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

The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

PubMed

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

2015-07-01

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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

In Silico Evaluation of Pharmacokinetic Optimization for Antimitogram-Based Clinical Trials.

PubMed

Haviari, Skerdi; You, Benoît; Tod, Michel

2018-04-01

Antimitograms are prototype in vitro tests for evaluating chemotherapeutic efficacy using patient-derived primary cancer cells. These tests might help optimize treatment from a pharmacodynamic standpoint by guiding treatment selection. However, they are technically challenging and require refinements and trials to demonstrate benefit to be widely used. In this study, we performed simulations aimed at exploring how to validate antimitograms and how to complement them by pharmacokinetic optimization. A generic model of advanced cancer, including pharmacokinetic-pharmacodynamic monitoring, was used to link dosing schedules with progression-free survival (PFS), as built from previously validated modules. This model was used to explore different possible situations in terms of pharmacokinetic variability, pharmacodynamic variability, and antimitogram performance. The model recapitulated tumor dynamics and standalone therapeutic drug monitoring efficacy consistent with published clinical results. Simulations showed that combining pharmacokinetic and pharmacodynamic optimization should increase PFS in a synergistic fashion. Simulated data were then used to compute required clinical trial sizes, which were 30% to 90% smaller when pharmacokinetic optimization was added to pharmacodynamic optimization. This improvement was observed even when pharmacokinetic optimization alone exhibited only modest benefit. Overall, our work illustrates the synergy derived from combining antimitograms with therapeutic drug monitoring, permitting a disproportionate reduction of the trial size required to prove a benefit on PFS. Accordingly, we suggest that strategies with benefits too small for standalone clinical trials could be validated in combination in a similar manner. Significance: This work offers a method to reduce the number of patients needed for a clinical trial to prove the hypothesized benefit of a drug to progression-free survival, possibly easing opportunities to evaluate

Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits

PubMed Central

Groll, Andreas H.; Gullick, Bryan M.; Petraitiene, Ruta; Petraitis, Vidmantas; Candelario, Myrna; Piscitelli, Stephen C.; Walsh, Thomas J.

2001-01-01

The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (Cmax) ± standard error of the mean increased from 16.01 ± 0.61 μg/ml at the 1-mg/kg dose to 105.52 ± 8.92 μg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 μg · h/ml, respectively. The mean apparent volume of distribution at steady state (Vdss) was 0.299 ± 0.011 liter/kg at the 1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vdss, there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi. PMID:11158761

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.

PubMed

Gonzalez, Daniel; Chamberlain, James M; Guptill, Jeffrey T; Cohen-Wolkowiez, Michael; Harper, Barrie; Zhao, Jian; Capparelli, Edmund V

2017-08-01

Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7) 0.133 *WT 0.75 ; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT 0.75 . No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.

Chance UK

ERIC Educational Resources Information Center

McGrath, Gracia

2003-01-01

Chance UK is a unique charity in the UK that specialises in mentoring programmes for primary schoolchildren with behavioural problems. It was founded in 1995 by a policeman, Chief Superintendent Paul Mathias, who believed that by stepping in early, young children with behavioural difficulties could be given the chance to develop the necessary…

Alpha-lipoic acid-stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study.

PubMed

Dhaundiyal, Ankit; Jena, Sunil K; Samal, Sanjaya K; Sonvane, Bhavin; Chand, Mahesh; Sangamwar, Abhay T

2016-12-01

This study was designed to demonstrate the potential of novel α-lipoic acid-stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX). α-lipoic acid-stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification-diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats. Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues. α-lipoic acid-stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects. © 2016 Royal Pharmaceutical Society.

A Randomised Cross-Over Pharmacokinetic Bioavailability Study of Synthetic versus Kiwifruit-Derived Vitamin C

PubMed Central

Carr, Anitra C.; Bozonet, Stephanie M.; Vissers, Margreet C. M.

2013-01-01

Kiwifruit are a rich source of vitamin C and also contain numerous phytochemicals, such as flavonoids, which may influence the bioavailability of kiwifruit-derived vitamin C. The aim of this study was to compare the relative bioavailability of synthetic versus kiwifruit-derived vitamin C using a randomised cross-over pharmacokinetic study design. Nine non-smoking males (aged 18–35 years) received either a chewable tablet (200 mg vitamin C) or the equivalent dose from gold kiwifruit (Actinidia chinensis var. Sungold). Fasting blood and urine were collected half hourly to hourly over the eight hours following intervention. The ascorbate content of the plasma and urine was determined using HPLC with electrochemical detection. Plasma ascorbate levels increased from 0.5 h after the intervention (P = 0.008). No significant differences in the plasma time-concentration curves were observed between the two interventions (P = 0.645). An estimate of the total increase in plasma ascorbate indicated complete uptake of the ingested vitamin C tablet and kiwifruit-derived vitamin C. There was an increase in urinary ascorbate excretion, relative to urinary creatinine, from two hours post intervention (P < 0.001). There was also a significant difference between the two interventions, with enhanced ascorbate excretion observed in the kiwifruit group (P = 0.016). Urinary excretion was calculated as ~40% and ~50% of the ingested dose from the vitamin C tablet and kiwifruit arms, respectively. Overall, our pharmacokinetic study has shown comparable relative bioavailability of kiwifruit-derived vitamin C and synthetic vitamin C. PMID:24284610

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

PubMed Central

Stern, Stephan T.; Stevens, David M.

2016-01-01

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. PMID:27670412

Ketorolac pharmacokinetics in experimental cirrhosis by bile duct ligation in the rat.

PubMed

Rivera-Espinosa, Liliana; Muriel, Pablo; Ordaz Gallo, Mónica; Pérez-Urizar, José; Palma-Aguirre, Antonio; Castañeda-Hernández, Gilberto

2003-01-01

The purpose of the present work was to study the pharmacokinetics of ketorolac, a poorly metabolized drug, in experimental cirrhosis. Cirrhosis was induced by bile duct ligation (BDL) for four weeks in male Wistar rats. Ketorolac was given intravenously (1 mg/kg ) or orally (3.2 mg/kg) to control (sham-operated) and BDL-rats. Determination of ketorolac in plasma was carried out by HPLC and estimation of pharmacokinetic parameters was performed by non-compartmental analysis. Indicators of liver damage and liver fibrosis were significantly increased (p < 0.05) in BDL compared to control rats. Experimental cirrhosis did not induce any significant alteration in intravenous ketorolac pharmacokinetics. Volume of distribution, clearance, AUC and t1/2 were similar in BDL and control animals. Notwithstanding, oral ketorolac bioavailability was significantly altered in BDL rats. AUC and Cmax were reduced, while tmax was prolonged, suggesting that both, the extent and the rate of ketorolac absorption were decreased. Results show that liver cirrhosis may result in significant pharmacokinetic alterations, even for poorly bio-transformed drugs, but that alterations may vary with the route of administration. In conclusion, uncritical generalizations on the effect of liver damage on drug kinetics should be avoided and systematic studies for every drug and every route of administration are thus recommended.

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

PubMed Central

Gao, Wenqing; Kim, Juhyun; Dalton, James T.

2007-01-01

Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators. PMID:16841196

Optical Coherence Tomography in the UK Biobank Study – Rapid Automated Analysis of Retinal Thickness for Large Population-Based Studies

PubMed Central

Grossi, Carlota M.; Foster, Paul J.; Yang, Qi; Reisman, Charles A.; Chan, Kinpui; Peto, Tunde; Thomas, Dhanes; Patel, Praveen J.

2016-01-01

Purpose To describe an approach to the use of optical coherence tomography (OCT) imaging in large, population-based studies, including methods for OCT image acquisition, storage, and the remote, rapid, automated analysis of retinal thickness. Methods In UK Biobank, OCT images were acquired between 2009 and 2010 using a commercially available “spectral domain” OCT device (3D OCT-1000, Topcon). Images were obtained using a raster scan protocol, 6 mm x 6 mm in area, and consisting of 128 B-scans. OCT image sets were stored on UK Biobank servers in a central repository, adjacent to high performance computers. Rapid, automated analysis of retinal thickness was performed using custom image segmentation software developed by the Topcon Advanced Biomedical Imaging Laboratory (TABIL). This software employs dual-scale gradient information to allow for automated segmentation of nine intraretinal boundaries in a rapid fashion. Results 67,321 participants (134,642 eyes) in UK Biobank underwent OCT imaging of both eyes as part of the ocular module. 134,611 images were successfully processed with 31 images failing segmentation analysis due to corrupted OCT files or withdrawal of subject consent for UKBB study participation. Average time taken to call up an image from the database and complete segmentation analysis was approximately 120 seconds per data set per login, and analysis of the entire dataset was completed in approximately 28 days. Conclusions We report an approach to the rapid, automated measurement of retinal thickness from nearly 140,000 OCT image sets from the UK Biobank. In the near future, these measurements will be publically available for utilization by researchers around the world, and thus for correlation with the wealth of other data collected in UK Biobank. The automated analysis approaches we describe may be of utility for future large population-based epidemiological studies, clinical trials, and screening programs that employ OCT imaging. PMID:27716837

A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours

PubMed Central

Undevia, Samir D.; Innocenti, Federico; Ramirez, Jacqueline; House, Larry; Desai, Apurva A.; Skoog, Linda A.; Singh, Deepti A.; Karrison, Theodore; Kindler, Hedy L.; Ratain, Mark J.

2009-01-01

Purpose To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose. Methods R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1–5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmaco-kinetic studies. Results Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma. Conclusions The recommended phase II doses are 850–1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes. PMID:18650079

Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after single and multiple oral administration: A comparative study in the rat.

PubMed

Gonçalves, Daniela; Alves, Gilberto; Fortuna, Ana; Soares-da-Silva, Patrício; Falcão, Amílcar

2017-05-15

Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n=8 per group) were orally treated with single (30, 60 or 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24h post-dosing through a cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration≤2h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30-90mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58-4.50h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. Copyright © 2017 Elsevier Inc. All rights reserved.

An HPLC tandem mass spectrometry for quantification of ET-26-HCl and its major metabolite in plasma and application to a pharmacokinetic study in rats.

PubMed

Chen, Xu; Zhang, Wensheng; Rios, Sandy; Morkos, Miriam B; Ye, Xiaoli; Li, Gen; Jiang, Xuehua; Wang, Zhijun; Wang, Ling

2018-02-05

ET-26-HCl is a new analog of etomidate, a short-acting anesthetic drug, with less adrenal cortex inhibition. The pharmacokinetics of ET-26-HCl in rats needs to be determined for future clinical trials in human subjects. In order to facilitate the pharmacokinetic study, a liquid chromatography based tandem mass spectrometric (HPLC-MS/MS) method was developed and validated for quantification of ET-26-HCl and its major metabolite, ET-26-acid. These two compounds and gabapentin (internal standard) were extracted using a protein precipitation method with methanol and detected by Multiple Reaction Monitoring of m/z transition of 275.6-170.9, 217.7-113.1, and 172.5-154.3 for ET-26-HCl, ET-26-acid, and gabapentin respectively. This method was validated in terms of sensitivity, linearity, reproducibility, and stability. The HPLC-MS/MS method was found linear over the concentration ranges of 21.76-4352ng/mL, and 18.62-3724ng/mL with LLOQ of 21.76 and 18.62ng/mL for ET-26-HCl and ET-26-acid respectively. The mean intra-day and inter-day accuracy was between 94.11-107.78%, while the precision was within the limit of 15.0% for all the quality control samples. A pharmacokinetic study was then conducted in rats following intravenous injection of 2.1, 4.2, and 8.4mg/kg. The linear pharmacokinetics of ET-26-HCl was observed over the dose range of 2.1-8.4mg/kg. The average terminal phase elimination half-lives were 0.87 and 1.03h for ET-26-HCl and ET-26-acid respectively. In summary, an HPLC-MS/MS method for quantification of ET-26-HCl in rat plasma has been developed and successfully applied to a pharmacokinetic study. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles

NASA Astrophysics Data System (ADS)

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

2015-11-01

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

Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans.

PubMed

Dolder, Patrick C; Schmid, Yasmin; Haschke, Manuel; Rentsch, Katharina M; Liechti, Matthias E

2015-06-24

The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice. We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects. Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1 ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4 ng/mL) were reached (median, range) 1.5 (0.5-4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans

PubMed Central

Dolder, Patrick C.; Schmid, Yasmin; Haschke, Manuel; Rentsch, Katharina M.

2016-01-01

Background: The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice. Methods: We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects. Results: Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4ng/mL) were reached (median, range) 1.5 (0.5–4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. Conclusions: These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide. PMID:26108222

Population Pharmacokinetics of Intranasal Scopolamine

NASA Technical Reports Server (NTRS)

Wu, L.; Chow, D. S. L.; Putcha, L.

2013-01-01

Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients.

PubMed

Moltó, José; Xinarianos, George; Miranda, Cristina; Pushpakom, Sudeep; Cedeño, Samandhy; Clotet, Bonaventura; Owen, Andrew; Valle, Marta

2013-07-01

Darunavir is a potent protease inhibitor of HIV. To enhance its pharmacokinetic profile, darunavir must be co-administered with ritonavir. There is wide inter-patient variability in darunavir pharmacokinetics among HIV-infected individuals, however. Darunavir is a known substrate for influx transporters, such as the 1A2 and the 1B1 members of the solute carrier organic anion transporter family (SLCO1A2, SLCO1B1), as well as for efflux transporters such as the multi-drug resistance protein 1 (MRP1). The aim of this study was to develop a semi-mechanistic population pharmacokinetic model for darunavir and ritonavir administered in HIV-infected adults. The desired model would incorporate patient characteristics and pharmacogenetic data contributing to variability in drug concentrations and also take into account the interaction between the two compounds. A population pharmacokinetic analysis was performed with 705 plasma samples from 75 Caucasian individuals receiving darunavir/ritonavir (600/100 mg twice daily) for at least 4 weeks. At least one full pharmacokinetic profile was obtained for each participant, and darunavir and ritonavir concentrations in plasma were determined by high performance liquid chromatography. Genotyping for 148 polymorphisms in genes coding for transporters or metabolizing enzymes was conducted by two methods: MALDI-TOF mass spectrometry and real-time polymerase chain reaction-based allelic discrimination. A population pharmacokinetic model was developed for darunavir and for ritonavir. The effect of single nucleotide polymorphisms on the post hoc individual pharmacokinetic parameters was first explored using graphic methods and regression analysis. Those covariates related to changes in darunavir or ritonavir pharmacokinetic parameters were then further evaluated using non-linear mixed effects modeling (NONMEM version VII). Darunavir and ritonavir pharmacokinetics were best described by a two- and one-compartment model, respectively, both

Nonlinear Pharmacokinetics of 5-Methoxy-N,N-dimethyltryptamine in MiceS⃞

PubMed Central

Shen, Hong-Wu; Jiang, Xi-Ling

2011-01-01

5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses. PMID:21464174

Pharmacokinetic and pharmacodynamic assessment of bioavailability for two prodrugs of methylprednisolone

PubMed Central

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

1997-01-01

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

Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

PubMed

Šíma, M; Pokorná, P; Hronová, K; Slanař, O

2015-01-01

Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

The Cleft Care UK study. Part 4: perceptual speech outcomes

PubMed Central

Sell, D; Mildinhall, S; Albery, L; Wills, A K; Sandy, J R; Ness, A R

2015-01-01

Structured Abstract Objectives To describe the perceptual speech outcomes from the Cleft Care UK (CCUK) study and compare them to the 1998 Clinical Standards Advisory Group (CSAG) audit. Setting and sample population A cross-sectional study of 248 children born with complete unilateral cleft lip and palate, between 1 April 2005 and 31 March 2007 who underwent speech assessment. Materials and methods Centre-based specialist speech and language therapists (SLT) took speech audio–video recordings according to nationally agreed guidelines. Two independent listeners undertook the perceptual analysis using the CAPS-A Audit tool. Intra- and inter-rater reliability were tested. Results For each speech parameter of intelligibility/distinctiveness, hypernasality, palatal/palatalization, backed to velar/uvular, glottal, weak and nasalized consonants, and nasal realizations, there was strong evidence that speech outcomes were better in the CCUK children compared to CSAG children. The parameters which did not show improvement were nasal emission, nasal turbulence, hyponasality and lateral/lateralization. Conclusion These results suggest that centralization of cleft care into high volume centres has resulted in improvements in UK speech outcomes in five-year-olds with unilateral cleft lip and palate. This may be associated with the development of a specialized workforce. Nevertheless, there still remains a group of children with significant difficulties at school entry. PMID:26567854

The Cleft Care UK study. Part 4: perceptual speech outcomes.

PubMed

Sell, D; Mildinhall, S; Albery, L; Wills, A K; Sandy, J R; Ness, A R

2015-11-01

To describe the perceptual speech outcomes from the Cleft Care UK (CCUK) study and compare them to the 1998 Clinical Standards Advisory Group (CSAG) audit. A cross-sectional study of 248 children born with complete unilateral cleft lip and palate, between 1 April 2005 and 31 March 2007 who underwent speech assessment. Centre-based specialist speech and language therapists (SLT) took speech audio-video recordings according to nationally agreed guidelines. Two independent listeners undertook the perceptual analysis using the CAPS-A Audit tool. Intra- and inter-rater reliability were tested. For each speech parameter of intelligibility/distinctiveness, hypernasality, palatal/palatalization, backed to velar/uvular, glottal, weak and nasalized consonants, and nasal realizations, there was strong evidence that speech outcomes were better in the CCUK children compared to CSAG children. The parameters which did not show improvement were nasal emission, nasal turbulence, hyponasality and lateral/lateralization. These results suggest that centralization of cleft care into high volume centres has resulted in improvements in UK speech outcomes in five-year-olds with unilateral cleft lip and palate. This may be associated with the development of a specialized workforce. Nevertheless, there still remains a group of children with significant difficulties at school entry. © The Authors. Orthodontics & Craniofacial Research Published by John Wiley & Sons Ltd.

Effect of hepatic impairment on the pharmacokinetics of a single dose of cilostazol.

PubMed

Bramer, S L; Forbes, W P

1999-01-01

The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100 mg were compared between individuals with impaired and normal liver function. The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial. 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B). Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods. Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%. Based on the results of the pharmacokinetic analysis, dose adjustment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered to patients with moderate or severe hepatic impairment.

Lack of sex-related differences in saquinavir pharmacokinetics in an HIV-seronegative cohort

PubMed Central

Robertson, Sarah M; Formentini, Elizabeth; Alfaro, Raul M; Natarajan, Ven; Falloon, Judith; Penzak, Scott R

2006-01-01

Aims To examine the influence of sex on steady-state saquinavir pharmacokinetics in HIV-seronegative volunteers administered saquinavir without a concomitant protease inhibitor. Methods Thirty-eight healthy volunteers (14 female) received saquinavir soft-gel capsules 1200 mg three times daily for 3 days to achieve steady-state conditions. Following administration of the 10th dose, blood was collected serially over 8 h for measurement of saquinavir plasma concentrations. Saquinavir pharmacokinetic parameter values were determined using noncompartmental methods and compared between males and females. CYP3A phenotype (using oral midazolam) and MDR-1 genotypes at positions 3435 and 2677 were determined for all subjects in order to characterize possible mechanisms for any observed sex-related differences. Results There was no significant difference in saquinavir AUC0−8 or any other pharmacokinetic parameter value between the sexes. These findings persisted after mathematically correcting for total body weight. The mean weight-normalized AUC0−8 was 29.9 (95% confidence interval 15.5, 44.3) and 29.8 (18.6, 40.9) ng h−1 ml−1 kg−1 for males and females, respectively. No significant difference in CYP3A phenotype was observed between the groups; likewise, the distribution of MDR-1 genotypes was similar for males and females. Conclusion In contrast to previous study findings, results from this investigation showed no difference in saquinavir pharmacokinetics between males and females. The discrepancy between our findings and those previously reported may be explained by the fact that we evaluated HIV-seronegative volunteers and administered saquinavir in the absence of concomitant protease inhibitors such as ritonavir. Caution must be exercised when extrapolating pharmacokinetic data from healthy volunteer studies (including sex-based pharmacokinetic differences) to HIV-infected populations or to patients receiving additional concurrent medications. PMID

[Microbiological and pharmacokinetic studies on flomoxef in ophthalmologic field].

PubMed

Ooishi, M; Sakaue, F; Oomomo, A; Tazawa, H

1989-05-01

Microbiological and pharmacokinetic studies were carried out on flomoxef (FMOX, 6315-S), a new oxacephem parenteral antibiotic, in the ophthalmologic field. The results obtained are summarized as follows. FMOX has a broad antimicrobial activity spectrum against Gram-positive and Gram-negative bacteria. The MIC distribution against Staphylococcus aureus isolated from clinical cases was less than or equal to 0.20 - greater than or equal to 100 micrograms/ml with the peak value of 0.39 micrograms/ml. Concentrations of FMOX in aqueous humor and ocular tissues were determined after intravenous injection of 50 mg/kg to rabbits. FMOX showed a peak level of 2.2 micrograms/ml in the aqueous humor at 1/2 hour after administration with the ratio to serum level of 3.4%. Levels of FMOX in external and internal ocular tissues were 12.7 - 76.5 micrograms/g, less than 0.8 - 34.4 micrograms/g (ml) at 1/2 hour after administration, respectively. From these results, we concluded that FMOX may be expected to be a useful and valuable agent against infections in the ophthalmologic field.

[Determination of plasma concentration of five phenolic acid by LC-MS/MS and study of pharmacokinetics in rats after Mailuoning injection].

PubMed

Wu, Ting; Zhang, Jun; Tan, Heng-Shan; Ju, Wen-Zheng; Xu, Xiang-Yang

2014-05-01

To establish a LC-MS/MS method for quantification of chlorogenic acid, caffeic acid, 3,4-DCQA, ferulic acid and cinnamic acid in rats plasma and study its pharmacokinetics after administration of Mailuoning injection at a single dose to rats. Plasma samples were acidified with hydrochloric acid and extracted with ethyl acetate. The analytes were determined by LC-MS-MS using a ZOBAX SB C18 column with a mobile phase of methanol-water (containing 2 mmol x L(-1) ammonium acetic) (60:40)at a flow rate of 0.5 mL x min(-1) and detected using ESI with negative ionization mode. Ions monitored in the multiple reaction monitoring (MRM) mode were m/z 353.1/191.0 [M-H]- for chlorogenic acid, m/z 178.9/134.9 [M-H]- for caffeic acid, m/z 515.2/353.0 [M-H]-for 3,4-DCQA, m/z 193.0/133.9 [M-H]-for ferulic acid, m/z 146.9/102.9 [M-H]- for cinnamic acid and m/z 246.0/125.8 [M-H]- for tinidazole (IS). After administration of Mailuoning injection at a single dose to eight Sprague-Dawley rats, the concentrations of chlorogenic acid, caffeic acid, 3,4-DCQA, ferulic acid and cinnamic acid in plasma were determined by LC-MS/MS method. The main pharmacokinetics parameters of measured data were caluculated by using DASver 1.0 software. The linear concentration ranges of the calibration curves for chlorogenic acid, caffeic acid, 3,4-DCQA and cinnamic acid were 2.006-1,027 microg x L(-1) (r = 0.999 6), 1.953-1,000 microg x L(-1) (r = 0.999 7), 28.51-1.459 x 10(4) microg x L(-1) (r = 0.998 9), 1.836-940.0, g x L(-1) (r = 0.997 7) and 4.780-2,447 microg x L(-1) (r = 0.998 6) respectively. The inner and inter-days relative standard deviations were both less than 5.0%, indicating legitimate precise and accuracy to the requirement of biological sample analysis. For chlorogenic acid, the pharmacokinetic parameter t1/2, AUC0-t, and CL were (49.78 +/- 12.81) min, (123.55 +/- 14.82) mg x min x L(-1) and (0.004 3 +/- 0.000 5) L x min(-1), respectively. For caffeic acid, the pharmacokinetic parameter t1

Health status of UK care home residents: a cohort study

PubMed Central

Gordon, Adam Lee; Franklin, Matthew; Bradshaw, Lucy; Logan, Pip; Elliott, Rachel; Gladman, John R.F.

2014-01-01

Background: UK care home residents are often poorly served by existing healthcare arrangements. Published descriptions of residents’ health status have been limited by lack of detail and use of data derived from surveys drawn from social, rather than health, care records. Aim: to describe in detail the health status and healthcare resource use of UK care home residents Design and setting: a 180-day longitudinal cohort study of 227 residents across 11 UK care homes, 5 nursing and 6 residential, selected to be representative for nursing/residential status and dementia registration. Method: Barthel index (BI), Mini-mental state examination (MMSE), Neuropsychiatric index (NPI), Mini-nutritional index (MNA), EuroQoL-5D (EQ-5D), 12-item General Health Questionnaire (GHQ-12), diagnoses and medications were recorded at baseline and BI, NPI, GHQ-12 and EQ-5D at follow-up after 180 days. National Health Service (NHS) resource use data were collected from databases of local healthcare providers. Results: out of a total of 323, 227 residents were recruited. The median BI was 9 (IQR: 2.5–15.5), MMSE 13 (4–22) and number of medications 8 (5.5–10.5). The mean number of diagnoses per resident was 6.2 (SD: 4). Thirty per cent were malnourished, 66% had evidence of behavioural disturbance. Residents had contact with the NHS on average once per month. Conclusion: residents from both residential and nursing settings are dependent, cognitively impaired, have mild frequent behavioural symptoms, multimorbidity, polypharmacy and frequently use NHS resources. Effective care for such a cohort requires broad expertise from multiple disciplines delivered in a co-ordinated and managed way. PMID:23864424

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

PubMed

Brown, Randall T; Nicholas, Christopher R; Cozzi, Nicholas V; Gassman, Michele C; Cooper, Karen M; Muller, Daniel; Thomas, Chantelle D; Hetzel, Scott J; Henriquez, Kelsey M; Ribaudo, Alexandra S; Hutson, Paul R

2017-12-01

Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. NCT02163707.

Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

PubMed

Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

2015-02-01

Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

Oseltamivir Population Pharmacokinetics in the Ferret: Model Application for Pharmacokinetic/Pharmacodynamic Study Design

PubMed Central

Reddy, Micaela B.; Yang, Kuo-Hsiung; Rao, Gauri; Rayner, Craig R.; Nie, Jing; Pamulapati, Chandrasena; Marathe, Bindumadhav M.; Forrest, Alan; Govorkova, Elena A.

2015-01-01

The ferret is a suitable small animal model for preclinical evaluation of efficacy of antiviral drugs against various influenza strains, including highly pathogenic H5N1 viruses. Rigorous pharmacokinetics/pharmacodynamics (PK/PD) assessment of ferret data has not been conducted, perhaps due to insufficient information on oseltamivir PK. Here, based on PK data from several studies on both uninfected and influenza-infected groups (i.e., with influenza A viruses of H5N1 and H3N2 subtypes and an influenza B virus) and several types of anesthesia we developed a population PK model for the active compound oseltamivir carboxylate (OC) in the ferret. The ferret OC population PK model incorporated delayed first-order input, two-compartment distribution, and first-order elimination to successfully describe OC PK. Influenza infection did not affect model parameters, but anesthesia did. The conclusion that OC PK was not influenced by influenza infection must be viewed with caution because the influenza infections in the studies included here resulted in mild clinical symptoms in terms of temperature, body weight, and activity scores. Monte Carlo simulations were used to determine that administration of a 5.08 mg/kg dose of oseltamivir phosphate to ferret every 12 h for 5 days results in the same median OC area under the plasma concentration-time curve 0–12 h (i.e., 3220 mg h/mL) as that observed in humans during steady state at the approved dose of 75 mg twice daily for 5 days. Modeling indicated that PK variability for OC in the ferret model is high, and can be affected by anesthesia. Therefore, for proper interpretation of PK/PD data, sparse PK sampling to allow the OC PK determination in individual animals is important. Another consideration in appropriate design of PK/PD studies is achieving an influenza infection with pronounced clinical symptoms and efficient virus replication, which will allow adequate evaluation of drug effects. PMID:26460484

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

PubMed

Franken, L G; de Winter, B C M; van Esch, H J; van Zuylen, L; Baar, F P M; Tibboel, D; Mathôt, R A A; van Gelder, T; Koch, B C P

2016-06-01

A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

One should avoid retro-orbital pharmacokinetic sample collections for intranasal dosing in rats: Illustration of spurious pharmacokinetics generated for anti-migraine drugs zolmitriptan and eletriptan.

PubMed

Patel, Harilal; Patel, Prakash; Modi, Nirav; Shah, Shaival; Ghoghari, Ashok; Variya, Bhavesh; Laddha, Ritu; Baradia, Dipesh; Dobaria, Nitin; Mehta, Pavak; Srinivas, Nuggehally R

2017-08-30

Because of the avoidance of first pass metabolic effects due to direct and rapid absorption with improved permeability, intranasal route represents a good alternative for extravascular drug administration. The aim of the study was to investigate the intranasal pharmacokinetics of two anti-migraine drugs (zolmitriptan and eletriptan), using retro-orbital sinus and jugular vein sites sampling. In a parallel study design, healthy male Sprague-Dawley (SD) rats aged between 8 and 12weeks were divided into groups (n=4 or 5/group). The animals of individual groups were dosed intranasal (~1.0mg/kg) and oral doses of 2.1mg/kg of either zolmitriptan or eletriptan. Serial blood sampling was performed from jugular vein or retro-orbital site and plasma samples were analyzed for drug concentrations using LC-MS/MS assay. Standard pharmacokinetics parameters such as T max , C max , AUC last , AUC 0-inf and T 1/2 were calculated and statistics of derived parameters was performed using unpaired t-test. After intranasal dosing, the mean pharmacokinetic parameters C max and AUC inf of zolmitriptan/eletriptan showed about 17-fold and 3-5-fold higher values for retro-orbital sampling as compared to the jugular vein sampling site. Whereas after oral administration such parameters derived for both drugs were largely comparable between the two sampling sites and statistically non-significant. In conclusion, the assessment of plasma levels after intranasal administration with retro-orbital sampling would result in spurious and misleading pharmacokinetics. Copyright © 2017 Elsevier B.V. All rights reserved.

Cross-Cultural Study of Information Processing Biases in Chronic Fatigue Syndrome: Comparison of Dutch and UK Chronic Fatigue Patients.

PubMed

Hughes, Alicia M; Hirsch, Colette R; Nikolaus, Stephanie; Chalder, Trudie; Knoop, Hans; Moss-Morris, Rona

2018-02-01

This study aims to replicate a UK study, with a Dutch sample to explore whether attention and interpretation biases and general attentional control deficits in chronic fatigue syndrome (CFS) are similar across populations and cultures. Thirty eight Dutch CFS participants were compared to 52 CFS and 51 healthy participants recruited from the UK. Participants completed self-report measures of symptoms, functioning, and mood, as well as three experimental tasks (i) visual-probe task measuring attentional bias to illness (somatic symptoms and disability) versus neutral words, (ii) interpretive bias task measuring positive versus somatic interpretations of ambiguous information, and (iii) the Attention Network Test measuring general attentional control. Compared to controls, Dutch and UK participants with CFS showed a significant attentional bias for illness-related words and were significantly more likely to interpret ambiguous information in a somatic way. These effects were not moderated by attentional control. There were no significant differences between the Dutch and UK CFS groups on attentional bias, interpretation bias, or attentional control scores. This study replicated the main findings of the UK study, with a Dutch CFS population, indicating that across these two cultures, people with CFS demonstrate biases in how somatic information is attended to and interpreted. These illness-specific biases appear to be unrelated to general attentional control deficits.

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

PubMed

Kukanich, Butch; Borum, Stacy L

2008-05-01

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

Moxifloxacin pharmacokinetics and pleural fluid penetration in patients with pleural effusion.

PubMed

Chatzika, Kalliopi; Manika, Katerina; Kontou, Paschalina; Pitsiou, Georgia; Papakosta, Despina; Zarogoulidis, Konstantinos; Kioumis, Ioannis

2014-01-01

The aim of this study was to evaluate the pharmacokinetics and penetration of moxifloxacin (MXF) in patients with various types of pleural effusion. Twelve patients with empyema/parapneumonic effusion (PPE) and 12 patients with malignant pleural effusion were enrolled in the study. A single-dose pharmacokinetic study was performed after intravenous administration of 400 mg MXF. Serial plasma (PL) and pleural fluid (PF) samples were collected during a 24-h time interval after drug administration. The MXF concentration in PL and PF was determined by high-performance liquid chromatography, and main pharmacokinetic parameters were estimated. Penetration of MXF in PF was determined by the ratio of the area under the concentration-time curve from time zero to 24 h (AUC24) in PF (AUC24PF) to the AUC24 in PL. No statistically significant differences in the pharmacokinetics in PL were observed between the two groups, despite the large interindividual variability in the volume of distribution, clearance, and elimination half-life. The maximum concentration in PF (CmaxPF) in patients with empyema/PPE was 2.23±1.31 mg/liter, and it was detected 7.50±2.39 h after the initiation of the infusion. In patients with malignant effusion, CmaxPF was 2.96±1.45 mg/liter, but it was observed significantly earlier, at 3.58±1.38 h (P<0.001). Both groups revealed similar values of AUC24PF (31.83±23.52 versus 32.81±12.66 mg·h/liter). Penetration of MXF into PF was similarly good in both patient groups (1.11±0.74 versus 1.17±0.39). Despite similar plasma pharmacokinetics, patients with empyema/parapneumonic effusion showed a significant delay in achievement of PF maximum MXF levels compared to those with malignant effusion. However, in both groups, the degree of MXF PF penetration and the on-site drug exposure, expressed by AUC24PF, did not differ according to the type of pleural effusion.

Dynamic Contrast-enhanced MR Imaging in Renal Cell Carcinoma: Reproducibility of Histogram Analysis on Pharmacokinetic Parameters

PubMed Central

Wang, Hai-yi; Su, Zi-hua; Xu, Xiao; Sun, Zhi-peng; Duan, Fei-xue; Song, Yuan-yuan; Li, Lu; Wang, Ying-wei; Ma, Xin; Guo, Ai-tao; Ma, Lin; Ye, Hui-yi

2016-01-01

Pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been increasingly used to evaluate the permeability of tumor vessel. Histogram metrics are a recognized promising method of quantitative MR imaging that has been recently introduced in analysis of DCE-MRI pharmacokinetic parameters in oncology due to tumor heterogeneity. In this study, 21 patients with renal cell carcinoma (RCC) underwent paired DCE-MRI studies on a 3.0 T MR system. Extended Tofts model and population-based arterial input function were used to calculate kinetic parameters of RCC tumors. Mean value and histogram metrics (Mode, Skewness and Kurtosis) of each pharmacokinetic parameter were generated automatically using ImageJ software. Intra- and inter-observer reproducibility and scan–rescan reproducibility were evaluated using intra-class correlation coefficients (ICCs) and coefficient of variation (CoV). Our results demonstrated that the histogram method (Mode, Skewness and Kurtosis) was not superior to the conventional Mean value method in reproducibility evaluation on DCE-MRI pharmacokinetic parameters (K trans & Ve) in renal cell carcinoma, especially for Skewness and Kurtosis which showed lower intra-, inter-observer and scan-rescan reproducibility than Mean value. Our findings suggest that additional studies are necessary before wide incorporation of histogram metrics in quantitative analysis of DCE-MRI pharmacokinetic parameters. PMID:27380733

[Diagnostic value of quantitative pharmacokinetic parameters and relative quantitative pharmacokinetic parameters in breast lesions with dynamic contrast-enhanced MRI].

PubMed

Sun, T T; Liu, W H; Zhang, Y Q; Li, L H; Wang, R; Ye, Y Y

2017-08-01

Objective: To explore the differential between the value of dynamic contrast-enhanced MRI quantitative pharmacokinetic parameters and relative pharmacokinetic quantitative parameters in breast lesions. Methods: Retrospective analysis of 255 patients(262 breast lesions) who was obtained by clinical palpation , ultrasound or full-field digital mammography , and then all lessions were pathologically confirmed in Zhongda Hospital, Southeast University from May 2012 to May 2016. A 3.0 T MRI scanner was used to obtain the quantitative MR pharmacokinetic parameters: volume transfer constant (K(trans)), exchange rate constant (k(ep))and extravascular extracellular volume fraction (V(e)). And measured the quantitative pharmacokinetic parameters of normal glands tissues which on the same side of the same level of the lesions; and then calculated the value of relative pharmacokinetic parameters: rK(rans)、rk(ep) and rV(e).To explore the diagnostic value of two pharmacokinetic parameters in differential diagnosis of benign and malignant breast lesions using receiver operating curves and model of logistic regression. Results: (1)There were significant differences between benign lesions and malignant lesions in K(trans) and k(ep) ( t =15.489, 15.022, respectively, P <0.05), there were no significant differences between benign lesions and malignant lesions in V(e)( t =-2.346, P >0.05). The areas under the ROC curve(AUC)of K(trans), k(ep) and V(e) between malignant and benign lesions were 0.933, 0.948 and 0.387, the sensitivity of K(trans), k(ep) and V(e) were 77.1%, 85.0%, 51.0% , and the specificity of K(trans), k(ep) and V(e) were 96.3%, 93.6%, 60.8% for the differential diagnosis of breast lesions if taken the maximum Youden's index as cut-off. (2)There were significant differences between benign lesions and malignant lesions in rK(trans), rk(ep) and rV(e) ( t =14.177, 11.726, 2.477, respectively, P <0.05). The AUC of rK(trans), rk(ep) and rV(e) between malignant and benign

UK-trained junior doctors' intentions to work in UK medicine: questionnaire surveys, three years after graduation

PubMed Central

Surman, Geraldine; Goldacre, Michael J

2017-01-01

Objective To report on the career intentions, three years after qualification, of 12 national cohorts of UK-trained doctors who qualified between 1974 and 2012, and, specifically, to compare recent UK medical graduates’ intentions to work in medicine in the UK with earlier graduates. Design Questionnaire surveys of cohorts of UK medical graduates defined by year of graduation. Setting UK. Participants 30,272 UK medical graduates. Main outcome measures Stated level of intention to pursue a long-term career in medicine in the UK. Results The response rate was 62% (30,272/48,927). We examined responses to the question ‘Apart from temporary visits abroad, do you intend to practise medicine in the United Kingdom for the foreseeable future?' Of doctors from UK homes, 90% had specified that they would ‘definitely or probably’ practise medicine in the UK in the surveys of 1977–1986, 81% in 1996–2011 and 64% in 2015. Those who said that they would probably or definitely not practise medicine in the UK comprised 5% in 1977–1986, 8% in 1996–2011 and 15% in 2015. Most who were not definite about a future career in UK medicine indicated that they would wish to practise medicine outside the UK rather than to leave medicine. Conclusions The wish to remain in UK medical practice in the 2015 survey was unprecedentedly low in this unique series of 40 years of surveys. PMID:29116902

UK-trained junior doctors' intentions to work in UK medicine: questionnaire surveys, three years after graduation.

PubMed

Surman, Geraldine; Goldacre, Michael J; Lambert, Trevor W

2017-12-01

Objective To report on the career intentions, three years after qualification, of 12 national cohorts of UK-trained doctors who qualified between 1974 and 2012, and, specifically, to compare recent UK medical graduates' intentions to work in medicine in the UK with earlier graduates. Design Questionnaire surveys of cohorts of UK medical graduates defined by year of graduation. Setting UK. Participants 30,272 UK medical graduates. Main outcome measures Stated level of intention to pursue a long-term career in medicine in the UK. Results The response rate was 62% (30,272/48,927). We examined responses to the question ' Apart from temporary visits abroad, do you intend to practise medicine in the United Kingdom for the foreseeable future?' Of doctors from UK homes, 90% had specified that they would 'definitely or probably' practise medicine in the UK in the surveys of 1977-1986, 81% in 1996-2011 and 64% in 2015. Those who said that they would probably or definitely not practise medicine in the UK comprised 5% in 1977-1986, 8% in 1996-2011 and 15% in 2015. Most who were not definite about a future career in UK medicine indicated that they would wish to practise medicine outside the UK rather than to leave medicine. Conclusions The wish to remain in UK medical practice in the 2015 survey was unprecedentedly low in this unique series of 40 years of surveys.

Population pharmacokinetics of abacavir in infants, toddlers and children.

PubMed

Zhao, Wei; Piana, Chiara; Danhof, Meindert; Burger, David; Della Pasqua, Oscar; Jacqz-Aigrain, Evelyne

2013-06-01

To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations. Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg(-1) day(-1) or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria. A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration-time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l(-1) and 6.1 mg h l(-1) for toddlers and infants, and 3.6 mg l(-1) and 8.7 mg h l(-1) for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling. The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012

Population pharmacokinetics of abacavir in infants, toddlers and children

PubMed Central

Zhao, Wei; Piana, Chiara; Danhof, Meindert; Burger, David; Della Pasqua, Oscar; Jacqz-Aigrain, Evelyne

2013-01-01

Aims To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations. Methods Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg−1 day−1 or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria. Results A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration–time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l−1 and 6.1 mg h l−1 for toddlers and infants, and 3.6 mg l−1 and 8.7 mg h l−1 for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling. Conclusions The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny. PMID:23126277

Development of a Physiologically Based Pharmacokinetic Model for Sinogliatin, a First-in-Class Glucokinase Activator, by Integrating Allometric Scaling, In Vitro to In Vivo Exploration and Steady-State Concentration-Mean Residence Time Methods: Mechanistic Understanding of its Pharmacokinetics.

PubMed

Song, Ling; Zhang, Yi; Jiang, Ji; Ren, Shuang; Chen, Li; Liu, Dongyang; Chen, Xijing; Hu, Pei

2018-04-06

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (C ss -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and C ss -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms. On this basis, an initial mechanistic PBPK model of sinogliatin was developed. The initial PBPK model was verified using observed data from a single ascending dose (SAD) study and further optimized with various strategies. The final model was validated by simulating sinogliatin pharmacokinetics under a fed condition. The validated model was applied to support a clinical drug-drug interaction (DDI) study design and to evaluate the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure. The two-species scaling method using rat and dog data (TS- rat,dog ) was the best AS method in predicting human systemic clearance in the central compartment (CL). The IVIVE method confirmed that sinogliatin was predominantly metabolized by cytochrome P450 (CYP) 3A4. The C ss -MRT method suggested dog pharmacokinetic profiles were more similar to human pharmacokinetic profiles. The estimated CL using the AS and IVIVE approaches was within 1.5-fold of that observed. The C ss -MRT method in dogs also provided acceptable prediction of human pharmacokinetic characteristics. For the PBPK approach, the 90% confidence intervals (CIs) of the simulated maximum concentration (C max ), CL, and area under the plasma concentration-time curve (AUC) of sinogliatin were within those observed and the 90% CI of simulated time to C max (t max ) was closed to that

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat.

PubMed

Kamel, Bishoy; Graham, Garry G; Williams, Kenneth M; Pile, Kevin D; Day, Richard O

2017-05-01

Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss /F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½ ) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9.4 ± 4.9 h. Febuxostat is administered once daily. The maximum (peak) plasma concentrations are approximately 100-fold greater than the trough concentrations. Consequently, there is no significant accumulation of the drug during multiple dose administration. There are few data on the pharmacokinetics of febuxostat in patients with gout. While the pharmacokinetic parameters are not affected by mild to moderate hepatic impairment, there is no consensus on whether renal impairment has any effect on the pharmacokinetics of febuxostat. Febuxostat is extensively metabolised by oxidation (approximately 35 %) and acyl glucuronidation (up to 40 %); febuxostat acyl glucuronides are cleared by the kidney. In healthy subjects treated with multiple doses of febuxostat 10-240 mg, the concentrations of serum urate are reduced by a maximum of about 80 %. The percentage reduction in the concentrations of serum urate is slightly less in gouty patients than in healthy subjects.

Experimental study of the anti-tumour activity and pharmacokinetics of arctigenin and its valine ester derivative.

PubMed

Cai, Enbo; Song, Xingzhuo; Han, Mei; Yang, Limin; Zhao, Yan; Li, Wei; Han, Jiahong; Tu, Shumei

2018-02-19

Arctigenin (ARG) is a functional active component that has important physiological and pharmacological activities. The anti-tumour and anti-inflammatory activities of ARG show good potential for application and development, but this material has the defect of low water solubility. In this experiment, the valine derivative of ARG (ARG-V) was designed and synthesized to overcome this disadvantage. The ARG amino acid, EDCI and DMAP were raw materials in the addition reaction, with a molar ratio of 1:2:2:0.5. The yield of ARG-V was up to 80%. ARG-V has strong anti-tumour activity in vivo and in vitro. The inhibitory rate of ARG-V was 69.2%, with less damage to the immune organs and different degrees of increased serum cytotoxicity. Moreover, the pharmacokinetics of ARG following oral administration and ARG-V following oral administration in rats were also studied. The C max and AUC values of ARG-V showed significant differences compared to ARG. The relative bioavailabilities of three doses of ARG-V compared to ARG were 664.7%, 741.5% and 812.9%. These pharmacokinetic results may be useful for further studies of the bioactive mechanism of ARG and provide a theoretical basic for clinical use.

Albendazole nanocrystals with improved pharmacokinetic performance in mice.

PubMed

Paredes, Alejandro J; Bruni, Sergio Sánchez; Allemandi, Daniel; Lanusse, Carlos; Palma, Santiago D

2018-02-01

Albendazole (ABZ) is a broad-spectrum antiparasitic agent with poor aqueous solubility, which leads to poor/erratic bioavailability and therapeutic failures. Here, we aimed to produce a novel formulation of ABZ nanocrystals (ABZNC) and assess its pharmacokinetic performance in mice. Results/methodology: ABZNC were prepared by high-pressure homogenization and spray-drying processes. Redispersion capacity and solid yield were measured in order to obtain an optimized product. The final particle size was 415.69±7.40 nm and the solid yield was 72.32%. The pharmacokinetic parameters obtained in a mice model for ABZNC were enhanced (p < 0.05) with respect to the control formulation. ABZNC with improved pharmacokinetic behavior were produced by a simple, inexpensive and potentially scalable methodology.

Age, nutritional status and INH acetylator status affect pharmacokinetics of anti-tuberculosis drugs in children.

PubMed

Ramachandran, G; Hemanth Kumar, A K; Bhavani, P K; Poorana Gangadevi, N; Sekar, L; Vijayasekaran, D; Banu Rekha, V V; Ramesh Kumar, S; Ravichandran, N; Mathevan, G; Swaminathan, S

2013-06-01

The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children. To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes. Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes. Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.

Study on pharmacokinetics of 3,4-divanillyltetrahydrofuran in rats by ultra-fast liquid chromatography/tandem mass spectrometry.

PubMed

Shan, Chen-Xiao; Cui, Xiao-Bing; Yu, Sheng; Chai, Chuan; Wen, Hong-Mei; Wang, Xin-Zhi; Sun, Xue

2016-01-01

3,4-Divanillyltetrahydrofuran is the main active ingredient of nettle root which can increase steroid hormones in the bloodstream for many of bodybuilders. To better understand its pharmacological activities, we need to determine its pharmacokinetic profiles. In this study, a rapid and sensitive ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method has been developed for the determination of 3,4-divanillyltetrahydrofuran in the plasma of rats. Chromatographic separation was performed on a C18 column at 40°C, with a gradient elution consisting of methanol and water containing 0.3% (v/v) formic acid at a flow rate of 0.8mL/min. The detection was performed using an electrospray triple-quadrupole MS/MS via positive ion multiple reaction monitoring mode. The lower limits-of-quantification determined were 0.5ng/mL. The intra- and inter-day precision (RSD%) was found to be within 15% and the accuracy (RE%) ranged from -4.0% to 7.0%. This simple yet sensitive method was fully validated and could be successfully applied to the study on pharmacokinetics of 3, 4-divanillyltetrahydrofuran. Copyright © 2015 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2012-01-01

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

All-atomistic molecular dynamics (AA-MD) studies and pharmacokinetic performance of PAMAM-dendrimer-furosemide delivery systems.

PubMed

Otto, Daniel P; de Villiers, Melgardt M

2018-06-13

Improvement of problematic dissolution and solubility properties of a model drug, furosemide, was investigated for poly(amidoamine) (PAMAM) dendrimer complexes of the drug. Full and half generation dendrimers with amino and ester terminals respectively, were studied. In vitro release performance of these complexes was investigated at drug loads ranging 5-60% using simulated gastric fluids. Full generation dendrimers accommodated higher drug loads, outperformed half-generation complexes, and free drug. Pharmacokinetic studies in rats indicated that the dendrimer complexes markedly improved in the bioavailability of the drug compared to the unformulated drug. The G3.0-PAMAM dendrimer complex showed a two-fold increase in C max and a 1.75-fold increase in AUC over the free drug. Additionally, T max was shortened from approximately 25 to 20 min. One of the first all-atomistic molecular dynamics (AA-MD) simulation studies was performed to evaluate low-generation dendrimer-drug complexes as well as its pharmacokinetic performance. AA-MD provided insight into the intermolecular interactions that take place between the dendrimer and drug. It is suggested that the dendrimer not only encapsulates the drug, but can also orientate the drug in stabilized dispersion to prevent drug clustering which could impact release and bioavailability negatively. AA-MD can be a useful tool to develop dendrimer-based drug delivery systems. Copyright © 2018. Published by Elsevier B.V.

Pharmacokinetics of testosterone cream applied to scrotal skin.

PubMed

Iyer, R; Mok, S F; Savkovic, S; Turner, L; Fraser, G; Desai, R; Jayadev, V; Conway, A J; Handelsman, D J

2017-07-01

Scrotal skin is thin and has high steroid permeability, but the pharmacokinetics of testosterone via the scrotal skin route has not been studied in detail. The aim of this study was to define the pharmacokinetics of testosterone delivered via the scrotal skin route. The study was a single-center, three-phase cross-over pharmacokinetic study of three single doses (12.5, 25, 50 mg) of testosterone cream administered in random sequence on different days with at least 2 days between doses to healthy eugonadal volunteers with endogenous testosterone suppressed by administration of nandrolone decanoate. Serum testosterone, DHT and estradiol concentrations were measured by liquid chromatograpy, mass spectrometry in extracts of serum taken before and for 16 h after administration of each of the three doses of testosterone cream to the scrotal skin. Testosterone administration onto the scrotal skin produced a swift (peak 1.9-2.8 h), dose-dependent (p < 0.0001) increase in serum testosterone with the 25 mg dose maintaining physiological levels for 16 h. Serum DHT displayed a time- (p < 0.0001), but not dose-dependent, increase in concentration reaching a peak concentration of 1.2 ng/mL (4.1 nm) at 4.9 h which was delayed by 2 h after peak serum testosterone. There were no significant changes in serum estradiol over time after testosterone administration. We conclude that testosterone administration to scrotal skin is well tolerated and produces dose-dependent peak serum testosterone concentration with a much lower dose relative to the non-scrotal transdermal route. © 2017 American Society of Andrology and European Academy of Andrology.

E-cigarette Nicotine Delivery: Data and Learnings from Pharmacokinetic Studies.

PubMed

Fearon, Ian M; Eldridge, Alison; Gale, Nathan; Shepperd, Christopher J; McEwan, Mike; Camacho, Oscar M; Nides, Mitch; McAdam, Kevin; Proctor, Christopher J

2017-01-01

E-cigarettes could potentially play a major role in tobacco harm reduction by delivering nicotine in a vapor containing significantly fewer toxicants than cigarette smoke and may aid smoking behavior changes such as reduction or cessation. We examined blood nicotine levels in smokers who were non-accustomed to e-cigarette use (Study 1) and accustomed e-cigarette users (Study 2). We compared nicotine levels when participants used a closed modular system e-cigarette to those when participants smoked a cigarette. In Study 1, Cmax (geometric mean (CV)) during a 5-minute puffing period (10 puffs, 30 seconds apart) was 13.4 (51.4) ng/ ml for a regular cigarette. The e-cigarette Cmax was significantly lower (p .05) at 2.5 (67.8) ng/ml. In Study 2, during a 5-minute ad libitum puffing period, cigarette Cmax was 7.2 (130.8) ng/mL, and it was 7.8 (108.2) ng/mL for the e-cigarette. Our data demonstrate heterogeneity of nicotine deliveries both between products and also with the same products used by different cohorts, eg, accustomed users versus smokers. Such differences must be taken into account when determining the likely behavioral impact, on smoking reduction and cessation, of nicotine delivery data and when planning e-cigarette nicotine pharmacokinetic studies.

Flip-flop pharmacokinetics – delivering a reversal of disposition: challenges and opportunities during drug development

PubMed Central

Yáñez, Jaime A; Remsberg, Connie M; Sayre, Casey L; Forrest, M Laird; Davies, Neal M

2011-01-01

Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined. PMID:21837267

Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients.

PubMed

Sime, Fekade B; Stuart, Janine; Butler, Jenie; Starr, Therese; Wallis, Steven C; Pandey, Saurabh; Lipman, Jeffrey; Roberts, Jason A

2018-06-01

To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period ( C max ), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC 0-∞ ), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution ( V ), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC 0-∞ was 39% of the values reported for heathy volunteers. The AUC 0-∞ was only 52% of the steady-state AUC 0-24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in

Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism.

PubMed

Goday Arno, Albert; Farré, Magí; Rodríguez-Morató, Jose; Ramon, Jose M; Pérez-Mañá, Clara; Papaseit, Esther; Civit, Ester; Langohr, Klaus; Lí Carbó, Marcel; Boix, David Benaiges; Nino, Olga Castañer; Le Roux, Juana Antonia Flores; Pera, Manuel; Grande, Luis; de la Torre, Rafael

2017-12-01

The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity).

KINPLOT: An Interactive Pharmacokinetics Graphics Program for Digital Computers.

ERIC Educational Resources Information Center

Wilson, Robert C.; And Others

1982-01-01

Inability to see the relevance of mathematics to understanding the time course of drugs in the body may discourage interest in pharmacokinetics. A UNC-developed computer graphics simulation program helps visualize the nature of pharmacokinetic-patient interactions, generates classroom handouts, and is used in the pharmaceuticals industry to…

Phytosomal curcumin: A review of pharmacokinetic, experimental and clinical studies.

PubMed

Mirzaei, Hamed; Shakeri, Abolfazl; Rashidi, Bahman; Jalili, Amin; Banikazemi, Zarrin; Sahebkar, Amirhossein

2017-01-01

Curcumin, a hydrophobic polyphenol, is the principal constituent extracted from dried rhizomes of Curcuma longa L. (turmeric). Curcumin is known as a strong anti-oxidant and anti-inflammatory agent that has different pharmacological effects. In addition, several studies have demonstrated that curcumin is safe even at dosages as high as 8g per day; however, instability at physiological pH, low solubility in water and rapid metabolism results in a low oral bioavailability of curcumin. The phytosomal formulation of curcumin (a complex of curcumin with phosphatidylcholine) has been shown to improve curcumin bioavailability. Existence of phospholipids in phytosomes leads to specific physicochemical properties such as amphiphilic nature that allows dispersion in both hydrophilic and lipophilic media. The efficacy and safety of curcumin phytosomes have been shown against several human diseases including cancer, osteoarthritis, diabetic microangiopathy and retinopathy, and inflammatory diseases. This review focuses on the pharmacokinetics as well as pharmacological and clinical effects of phytosomal curcumin. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design.

PubMed

Kipper, Karin; Barker, Charlotte I S; Standing, Joseph F; Sharland, Mike; Johnston, Atholl

2018-01-01

Penicillins are widely used to treat infections in children; however, the evidence is continuing to evolve in defining the optimal dosing. Modern pediatric pharmacokinetic study protocols frequently favor opportunistic, "scavenged" sampling. This study aimed to develop a small-volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modeling, to investigate the suitability of scavenged sampling strategies. Using a rapid ultrahigh-performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin, and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modeling was evaluated. All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 h, remaining in the range of 98 to 103% of the original concentration. More-rapid analyte degradation had already occurred after 4 h, with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 h. Modeling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance. Five common penicillins can now be measured in a single low-volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modeling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring. Copyright © 2017 American Society for Microbiology.

The pharmacokinetics of oxypurinol in people with gout

PubMed Central

Stocker, Sophie L; McLachlan, Andrew J; Savic, Radojka M; Kirkpatrick, Carl M; Graham, Garry G; Williams, Kenneth M; Day, Richard O

2012-01-01

AIMS Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations. METHODS Non-linear mixed effects modelling was applied to concentration–time data from 155 gouty patients with demographic, medical history and renal transporter genotype information. RESULTS A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration–time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/Fm) from 65% to 29%. CL/Fm for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h−1, respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines. CONCLUSIONS In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment. PMID:22300439

Pharmacokinetics and concentration–effect relationship of adalimumab in rheumatoid arthritis

PubMed Central

Ternant, David; Ducourau, Emilie; Fuzibet, Piéra; Vignault, Céline; Watier, Hervé; Lequerré, Thierry; Le Loët, Xavier; Vittecoq, Olivier; Goupille, Philippe; Mulleman, Denis; Paintaud, Gilles

2015-01-01

Aims This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration–effect relationship of adalimumab using pharmacokinetic–pharmacodynamic (PK–PD) modelling in patients with rheumatoid arthritis (RA). Methods Adalimumab PK and PK–PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated. Results Thirty patients treated for RA were analysed. The following pharmacokinetic and PK–PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd/F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day−1 (17%); first-order absorption rate (ka) = 0.28 day−1; CRP input (kin) = 22.0 mg l−1 day−1 (65%); adalimumab concentration leading to a 50% decrease in kin (C50) = 3.6 mg l−1 (88%); baseline DAS28 (DAS0) = 5.5 mg l−1 (11%); and adalimumab concentration leading to 50% decrease of DAS0 (IC50) = 11.0 mg l−1 (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection. Conclusions This is the first study to describe adalimumab pharmacokinetics and the concentration–effect relationship in RA. A 160 mg loading dose may lead to an increased benefit from treatment in RA patients. PMID:25223394

Pharmacokinetic analysis of multi PEG-theophylline conjugates.

PubMed

Grassi, Mario; Bonora, Gian Maria; Drioli, Sara; Cateni, Francesca; Zacchigna, Marina

2012-10-01

In the attempt of prolonging the effect of drugs, a new branched, high-molecular weight multimeric poly(ethylene glycol) (MultiPEG), synthesized with a simple assembling procedure that devised the introduction of functional groups with divergent and selective reactivity, was employed as drug carrier. In particular, the attention was focused on the study of theophylline (THEO) and THEO-MultiPEG conjugates pharmacokinetic after oral administration in rabbit. Pharmacokinetic behavior was studied according to an ad hoc developed mathematical model accounting for THEO-MultiPEG in vivo absorption and decomposition into drug (THEO) and carrier (MultiPEG). The branched high-molecular weight MultiPEG proved to be a reliable drug delivery system able to prolong theophylline staying in the blood after oral administration of a THEO-MultiPEG solution. The analysis of experimental data by means of the developed mathematical model revealed that the prolongation of THEO effect was essentially due to the low THEO-MultiPEG permeability in comparison to that of pure THEO. Copyright © 2012 Elsevier Ltd. All rights reserved.

Lungs deposition and pharmacokinetic study of submicron budesonide particles in Wistar rats intended for immediate effect in asthma.

PubMed

Rauf, Abdul; Bhatnagar, Aseem; Sisodia, S S; Khar, Roop K; Ahmad, Farhan J

2017-01-01

The purpose of the present investigation was to study the aerosolization, lungs deposition and pharmacokinetic study of inhalable submicron particles of budesonide in male Wistar rats. Submicron particles were prepared by antisolvent nanoprecipitation method and freeze-dried to obtain free flowing powder. The freeze-drying process yielded dry powder with desirable aerodynamic properties for inhalation therapy. An in-house model inhaler was designed to deliver medicine to lungs, optimized at dose level of 10 mg for 30 sec of fluidization. The in vitro aerosolization study demonstrates that submicron particles dissolve faster with improved aerosolization effect as compared to micronized budesonide. Both submicron and micron particles were compared for in vivo lungs deposition. The results showed that relatively high quantity of submicron particles reaches deep into the lungs as compared to micron particles. Most pronounced effect observed with submicron particles from pharmacokinetic parameters was the enhancement in peak plasma concentration (C max ) by 28.85 %, and increase in area under concentration curve (AUC 0-8h ) by 30.33 % compared to micron sized particles. The results suggested that developed submicronized formulation of budesonide can be used for pulmonary drug delivery for high deposition to deep lungs tissues.

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