Comparison of the Predictability of Human Hepatic Clearance for Organic Anion Transporting Polypeptide Substrate Drugs Between Different In Vitro-In Vivo Extrapolation Approaches.

Prediction of human pharmacokinetic profiles of drug candidates is an essential step toward first-in-human studies. However, it remains difficult to quantitatively predict hepatic clearance, particularly when hepatic uptake is mediated by transporter(s). Using 15 organic anion transporting polypeptide (OATP) substrate drugs, we tested 3 in vitro-in vivo extrapolation (IVIVE) approaches to predict overall hepatic intrinsic clearance in vivo (CL). IVIVE approaches involved metabolic intrinsic clearance in human liver microsomes (CL) with or without hepatocyte-to-buffer maximum unbound concentration ratio (K) correction and uptake intrinsic clearance at 37°C (PS) in human hepatocyte suspensions. K and PS values were determined in 2 hepatocyte batches, and all tested compounds showed temperature-dependent uptake, consistent with the fact of transporter-mediated uptake. CL substantially underestimated CL. By multiplying CL by K values, the prediction performance was much improved; however, in vitro-in vivo correlation was poor. Among the IVIVE approaches, PS showed the most robust correlation with CL, and one of the hepatocyte batches could predict CL with a minimal empirical scaling factor. These results suggested IVIVE with hepatic uptake clearance determined in hepatocyte suspensions as one of the most practical approaches for predicting CL of OATP substrate drugs.