Received for publication March 5, 2007.
Revised May 9, 2007.
Accepted for publication July 3, 2007.

Prediction of Human Pharmacokinetics Using Physiologically Based Modelling: A Retrospective Analysis of 26 Clinically Tested Drugs

Abstract

The aim of this study was to evaluate different physiologically based modelling 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 (Vss). This was compared with a strategy that combined predicted and experimentally determined in vivo rat P_tp data (Method Vd2). Best Vss 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). Vss predictions from physicochemical input alone were poor (32% within 2-fold). Apparent 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), while strong bias was seen using both blood and microsomal or hepatocyte binding (Method CL1, 53% within 2-fold). The PBPK model which combined Method Vd2 and CL2 yielded most accurate predictions of in vivo terminal half-life (69% within 2-fold). The Gastroplus ACAT 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.

Key words: clinical pharmacokinetics, drug clearance, drug disposition, in vitro-in vivo prediction, oral absorption, physiologically-based pharmacokinetics

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