Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

A. Kenneth MacLeod, Kevin-Sebastien Coquelin, Leticia Huertas, Frederick R.C. Simeons, Jennifer Riley, Patricia Casado, Laura Guijarro, Ruth Casanueva, Laura Frame, Erika G. Pinto , Liam Ferguson, Christina Duncan , Nicole Mutter, Yoko Shishikura, Colin J. Henderson , David Cebrian, C. Roland Wolf, and Kevin D. Read.

PNAS 121(7) e2315069121


A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily (“8HUM”) can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery.