Prediction of human pharmacokinetics using physiologically based modeling: a retrospective analysis of 26 clinically tested drugs.
نویسندگان
چکیده
The aim of this study was to evaluate different physiologically based modeling strategies for the prediction of human pharmacokinetics. Plasma profiles after intravenous and oral dosing were simulated for 26 clinically tested drugs. Two mechanism-based predictions of human tissue-to-plasma partitioning (P(tp)) from physicochemical input (method Vd1) were evaluated for their ability to describe human volume of distribution at steady state (V(ss)). This method was compared with a strategy that combined predicted and experimentally determined in vivo rat P(tp) data (method Vd2). Best V(ss) predictions were obtained using method Vd2, providing that rat P(tp) input was corrected for interspecies differences in plasma protein binding (84% within 2-fold). V(ss) predictions from physicochemical input alone were poor (32% within 2-fold). Total body clearance (CL) was predicted as the sum of scaled rat renal clearance and hepatic clearance projected from in vitro metabolism data. Best CL predictions were obtained by disregarding both blood and microsomal or hepatocyte binding (method CL2, 74% within 2-fold), whereas strong bias was seen using both blood and microsomal or hepatocyte binding (method CL1, 53% within 2-fold). The physiologically based pharmacokinetics (PBPK) model, which combined methods Vd2 and CL2 yielded the most accurate predictions of in vivo terminal half-life (69% within 2-fold). The Gastroplus advanced compartmental absorption and transit model was used to construct an absorption-disposition model and provided accurate predictions of area under the plasma concentration-time profile, oral apparent volume of distribution, and maximum plasma concentration after oral dosing, with 74%, 70%, and 65% within 2-fold, respectively. This evaluation demonstrates that PBPK models can lead to reasonable predictions of human pharmacokinetics.
منابع مشابه
Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations
The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recognized by the regulatory bodies. Physiologically based pharmacokinetic (PBPK) modeling offers an attractive platform to quantify anticipated changes in the pharmacokinetics (PKs) of drugs during pregnancy. Recent publications applying a pregnancy PBPK module to the prediction of maternal and fetal expos...
متن کاملDEVELOPMENT OF A PHYSIOLOGICALLY BASED TOXICOKINETIC MODEL FOR HUMAN EXPOSURE RISK ASSESSMENT OF METHYLENE DIPHENYL DIISOCYANATE(MDI)
Introduction: Given the lack of a developed physiologically based toxicokinetic (PBTK) model for human systemic exposure assessment of methylene diisocyanate (MDI) and prediction of its urinary metabolites, this study aims to develop a PBTK model for exposure risk assessment of MDI. Methods and Materials: In this study, to assess the potential exposure to the MDI, a PBTK model was constructed ...
متن کاملDmd052803 1994..2003
Physiologically based pharmacokinetic modeling and simulation can be used to predict the pharmacokinetics of drugs in human populations and to explore the effects of varying physiologic parameters that result from aging, ethnicity, or disease. In addition, the effects of concomitant medications on drug exposure can be investigated; prediction of the magnitude of drug interactions can impact reg...
متن کاملThe impact of hepatic uptake on the pharmacokinetics of organic anions.
The disposition of seven marketed and two AstraZeneca acid (organic anion) compounds with a range of volume of distribution at steady state (V(ss)) and clearance have been profiled in rat and dog. Pharmacokinetic (PK) parameters along with liver and muscle tissue levels were collected, and their contributions to total V(ss) were calculated. The physiologically based prediction of V(ss) correlat...
متن کاملPhysiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction
Herb-drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb-drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulate...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 35 10 شماره
صفحات -
تاریخ انتشار 2007