Quantitative prediction of CYP2C9-mediated drug disposition using humanized mice.Drug Metab Dispos 2025 Dec; 53(12):100185.DM
Drug clearance and drug-drug interactions (DDIs) are important in the pharmacokinetic assessment of investigational drugs, yet predicting in vivo fraction metabolized (fm) and DDI intensity remains challenging, particularly for low-clearance compounds. This study demonstrates how human liver chimeric mice (hu-PXB mice) can predict CYP2C9-mediated drug disposition for low-clearance compounds in humans. To estimate human in vitro CYP2C9 fraction metabolized (fm,CYP2C9,in vitro), 3 CYP2C9 substrates (phenytoin, tolbutamide, and warfarin) were incubated in human hepatocytes with or without sulfaphenazole (CYP2C9 inhibitor). The fm,CYP2C9,in vitro was calculated based on hepatic intrinsic clearance. For in vivo estimation (fm,CYP2C9,in vivo), clinical DDI data obtained using CYP2C9 inhibitors were analyzed to calculate fm,CYP2C9,in vivo based on observed clearance changes. To evaluate human DDI predictability, the 3 drugs were administered intravenously to hu-PXB and SCID mice with or without CYP2C9 inhibitors (sulfaphenazole or tienilic acid). Clearance changes were calculated and compared among humans, hu-PXB mice, and SCID mice. Results showed that fm,CYP2C9,in vitro values for phenytoin and tolbutamide were overestimated compared to fm,CYP2C9,in vivo, whereas warfarin could not be evaluated under current conditions. Hu-PXB mice demonstrated a better correlation with humans in both clearance changes and absolute values compared to SCID mice. Notably, hu-PXB mice predicted CYP2C9-mediated DDI magnitude within 15% of clinical values and predicted clearance for CYP2C9 substrates within 2-fold of clinical values. These findings establish hu-PXB mice as a reliable preclinical model for predicting human CYP2C9-mediated drug disposition. SIGNIFICANCE STATEMENT: Human liver chimeric mice can accurately predict the clearance and magnitude of drug-drug interaction for CYP2C9 substrate drugs. Findings from humanized mice enable the selection of better candidates in drug discovery and facilitate the design of efficient clinical trials for investigational drugs.
