| Source: |
MacLeod, A K, Coquelin, K-S, Huertas, L, Simeons, F R C, Riley, J, Casado, P, Guijarro, L, Casanueva, R, Frame, L, Pinto, E G, Ferguson, L, Duncan, C, Mutter, N, Shishikura, Y, Henderson, C J, Cebrian, D, Wolf, C R & Read, K D 2024, 'Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism', Proceedings of the National Academy of Sciences, vol. 121, no. 7, 2315069121, pp. 1-12. https://doi.org/10.1073/pnas.2315069121 |
| Description: |
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. |