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

A bstract Challenges/problems for in vitro methodologies 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 (CL int ) and fraction unbound in plasma (f u ) between laboratories were selected. The average and maximum ratios between highest and lowest reported predicted in vivo hepatic metabolic clearance (CL H ) for the drugs were 529- and 2436-fold, respectively. The in vivo CL H was predicted using in vitro CL int and f u data from the various highly sources and using our in silico methodology. The main aim was to compare the predictive accuracies for the in vitro and in silico methodologies. Prediction errors for in vitro methodology ranged from 1.1-to 578-fold, with an average of 150-fold for lowest predicted estimates and 16-fold for highest predicted estimates. The in vitro based predictions produced 36-to 38-fold higher average and maximum prediction errors than the in silico methodology, respectively. Mean and maximum in silico prediction errors were 4.2- and 15-fold, respectively, which is consistent with earlier results. In contrast to the in vitro methodology the in silico models did not predict high hepatic extraction ratio for drugs with low CL H . Overall, the in silico method clearly outperformed in vitro data for prediction of CL H in man for 10 drugs with large interlaboratory variability.