Shared learning from a physiologically based pharmacokinetic modeling strategy for human pharmacokinetics prediction through retrospective analysis of Genentech compounds.

The quantitative prediction of human pharmacokinetics (PK) including the PK profile and key PK parameters are critical for early drug development decisions, successful phase I clinical trials, and the establishment of a range of doses to enable phase II clinical dose selection. Here, we describe an approach employing physiologically based pharmacokinetic (PBPK) modeling (Simcyp) to predict human PK and to validate its performance through retrospective analysis of 18 Genentech compounds for which clinical data are available. In short, physicochemical parameters and in vitro data for preclinical species were integrated using PBPK modeling to predict the in vivo PK observed in mouse, rat, dog, and cynomolgus monkey. Through this process, the in vitro to in vivo extrapolation (IVIVE) was determined and then incorporated into PBPK modeling in order to predict human PK. Overall, the prediction obtained using this PBPK-IVIVE approach captured the observed human PK profiles of the compounds from the dataset well. The predicted Cmax was within 2-fold of the observed Cmax for 94% of the compounds while the predicted area under the curve (AUC) was within 2-fold of the observed AUC for 72% of the compounds. Additionally, important IVIVE trends were revealed through this investigation, including application of scaling factors determined from preclinical IVIVE to human PK prediction for each molecule. Based upon the analysis, this PBPK-based approach now serves as a practical strategy for human PK prediction at the candidate selection stage at Genentech.