In silicopredictions of the hepatic metabolic clearance in humans for 10 drugs with highly variablein vitropharmacokinetics

Abstract

AbstractChallenges/problems forin vitromethodologies for prediction of human clinical pharmacokinetics include inter- and intra-laboratory variability, and common occurance of high limits of quantification, low recovery, low parameter validity and low reproducibility. In this study, 10 drugs with substantial differences in human hepatocyte intrinsic metabolic clearance (CLint) and fraction unbound in plasma (fu) between laboratories were selected. The average and maximum ratios between highest and lowest reported predictedin vivohepatic metabolic clearance (CLH) for the drugs were 529- and 2436-fold, respectively. Thein vivoCLHwas predicted usingin vitroCLintand fudata from the various highly sources and using ourin silicomethodology. The main aim was to compare the predictive accuracies for thein vitroandin silicomethodologies. Prediction errors forin vitromethodology ranged from 1.1-to 578-fold, with an average of 150-fold for lowest predicted estimates and 16-fold for highest predicted estimates. Thein vitrobased predictions produced 36-to 38-fold higher average and maximum prediction errors than thein silicomethodology, respectively. Mean and maximumin silicoprediction errors were 4.2- and 15-fold, respectively, which is consistent with earlier results. In contrast to thein vitromethodology thein silicomodels did not predict high hepatic extraction ratio for drugs with low CLH. Overall, thein silicomethod clearly outperformedin vitrodata for prediction of CLHin man for 10 drugs with large interlaboratory variability.