Prediction of human pharmacokinetics for low-clearance compounds using pharmacokinetic data from chimeric mice with humanized livers.

Development of low-clearance (CL) compounds that are slowly metabolized is a major goal in the pharmaceutical industry. However, the pursuit of low intrinsic CL (CLint ) often leads to significant challenges in evaluating the pharmacokinetics of such compounds. Although in vitro-in vivo extrapolation is widely used to predict human CL, its application has been limited for low-CLint compounds because of the low turnover of parent compounds in metabolic stability assays. To address this issue, we focused on chimeric mice with humanized livers (PXB-mice), which have been increasingly reported to accurately predict human CL in recent years. The predictive accuracy for nine low-CLint compounds with no significant turnover in a human hepatocyte assay was investigated using PXB-mouse methods, such as single-species allometric scaling (PXB-SSS) approach and a novel physiologically based scaling (PXB-PBS) approach that assumes that the CLint per hepatocyte is equal between humans and PXB-mice. The percentages of compounds with predicted CL within 2- and 3-fold ranges of the observed CL for low-CLint compounds were 89% and 100%, respectively, for both PXB-SSS and PXB-PBS approaches. Moreover, the predicted CL was mostly consistent among the methods. Conversely, the percentages of compounds with predicted CL within 2- and 3-fold ranges of the observed CL for low-CLint compounds were 50% and 63%, respectively, for multispecies allometric (MA) scaling. Overall, these PXB-mouse methods were much more accurate than conventional MA scaling approaches, suggesting that PXB-mice are useful tools for predicting the human CL of low-CLint compounds that are slowly metabolized.