Quantitative prediction of CYP3A‐mediated drug–drug interactions by correctly estimating fraction metabolized using human liver chimeric mice

Abstract

Background and Purpose Fraction metabolized ( f m ) and fraction transported ( f t ) are important for understanding drug–drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo f m due to inability to reflect the f t by efflux transporters ( f t,efflux ). This study demonstrates how CYP3A‐mediated DDI for CYP3A/P‐gp substrates can be predicted using Hu‐PXB mice as human liver chimeric mice. Experimental Approach For estimating human in vitro f m by CYP3A enzyme ( f m,CYP3A,in vitro ), six drugs, including CYP3A/P‐gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated f m,CYP3A,in vitro based on hepatic intrinsic clearance. To estimate human in vivo f m,CYP3A ( f m,CYP3A,in vivo ), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated f m,CYP3A,in vivo using the change of total clearance (CL total ). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu‐PXB and SCID mice with or without ketoconazole. We calculated the change of CL total caused by ketoconazole. We compared the CL total change in humans with that in Hu‐PXB and SCID mice. Key Results The f m,CYP3A,in vitro was overestimated compared to the f m,CYP3A,in vivo . Hu‐PXB mice showed much better correlation in the change of CL total with humans ( R 2 = 0.95) compared to SCID mice ( R 2 = 0.0058). Conclusions and Implications CYP3A‐mediated DDI can be predicted by correctly estimating human f m,CYP3A,in vivo using Hu‐PXB mice. These mice could be useful predicting hepatic f m and f t,efflux .

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