The Impact of Reference Data Selection for the Prediction Accuracy of Intrinsic Hepatic Metabolic Clearance

In vitro-in vivo prediction results for hepatic metabolic clearance (CL_H) and intrinsic CL_H (CL_int) vary widely among studies. Reasons are not fully investigated and understood. The possibility to select favorable reference data for in vivo CL_H and CL_int and unbound fraction in plasma (f_u) is among possible explanations. The main objective was to investigate how reference data selection influences log in vitro and in vivo CL_int-correlations (r²). Another aim was to make a head-to-head comparison vs an in silico prediction method. Human hepatocyte CL_int-data for 15 compounds from two studies were selected. These were correlated to in vivo CL_int estimated using different reported CL_H- and f_u-estimates. Depending on the choice of reference data, r² from two studies were 0.07 to 0.86 and 0.06 to 0.79. When using average reference estimates a r² of 0.62 was achieved. Inclusion of two outliers in one of the studies resulted in a r² of 0.38, which was lower than the predictive accuracy (q²) for the in silico method (0.48). In conclusion, the selection of reference data appears to play a major role for demonstrated predictions and the in silico method showed higher accuracy and wider range than hepatocytes for human in vivo CL_int-predictions.