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

ABSTRACT: 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 (CL_int ) 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-CL_int 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-CL_int compounds with no significant turnover in a human hepatocyte assay was investig

SUBMITTER: Yoshida K 

PROVIDER: S-EPMC8742647 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature