Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism
Annette MacLeod, Kevin-Sebastien Coquelin, Leticia Huertas, Frederick R. C. Simeons, Jennifer Riley, Patricia Casado, Laura Guijarro, Ruth Casanueva, Laura Frame, Érika G. Pinto, Liam Ferguson, Christina Duncan, Nicole Mutter, Yoko Shishikura, Colin J. Henderson, David Cebrián, C. Roland Wolf, Kevin D. Read
Abstract
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.