Comparison of methods for the prediction of human clearance from hepatocyte intrinsic clearance for a set of reference compounds and an external evaluation set

Abstract1. We compared direct scaling, regression model equation and the so-called “Poulin et al.” methods to scale clearance (CL) from in vitro intrinsic clearance (CLint) measured in human hepatocytes using two sets of compounds. One reference set comprised of 20 compounds with known elimination pathways and one external evaluation set based on 17 compounds development in Merck (MS).2. A 90% prospective confidence interval was calculated using the reference set. This interval was found relevant for the regression equation method. The three outliers identified were justified on the basis of their elimination mechanism.3. The direct scaling method showed a systematic underestimation of clearance in both the reference and evaluation sets. The “Poulin et al.” and the regression equation methods showed no obvious bias in either the reference or evaluation sets.4. The regression model equation was slightly superior to the “Poulin et al.” method in the reference set and showed a better absolute average fold er...