Evaluation of the human prediction of clearance from hepatocyte and microsome intrinsic clearance for 52 drug compounds

We compare three different approaches to scale clearance (CL) from human hepatocyte and microsome CLint (intrinsic CL) for 52 drug compounds.By using the well-stirred model with protein binding included only 11% and 30% of the compounds were predicted within 2-fold and the average absolute fold errors (AAFE) for the predictions were 5.9 and 4.1 for hepatocytes and microsomes, respectively.When predictions were performed without protein binding, 59% of the compounds were predicted within 2-fold using either hepatocytes or microsomes and the AAFE was 2.2 and 2.3, respectively.For hepatocytes and microsomes there were significant correlations (P = 8.7 × 10−13, R2 = 0.72; P = 2.8 × 10−9, R2 = 0.61) between predicted CLint in vivo (obtained from in vitro CLint) and measured CLint in vivo (obtained using the well-stirred model). When CL was calculated from the regression, 76% and 70% of the compounds were predicted within 2-fold and the AAFE was 1.6 and 1.8 for hepatocytes and microsomes, respectively. We demon...