Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism.
A Kenneth MacLeodKevin-Sebastien CoquelinLeticia HuertasFrederick R C SimeonsJennifer RileyPatricia CasadoLaura GuijarroRuth CasanuevaLaura FrameErika G PintoLiam FergusonChristina DuncanNicole MutterYoko ShishikuraLesley A McLaughlinDavid CebrianC Roland WolfKevin D ReadPublished in: Proceedings of the National Academy of Sciences of the United States of America (2024)
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.
Keyphrases
- drug discovery
- wild type
- mycobacterium tuberculosis
- mouse model
- infectious diseases
- trypanosoma cruzi
- mental health
- primary care
- adverse drug
- high fat diet induced
- genome wide
- multidrug resistant
- monoclonal antibody
- metabolic syndrome
- emergency department
- pulmonary tuberculosis
- type diabetes
- genome wide identification