An Extensively Humanized Mouse Model to Predict Pathways of Drug Disposition and Drug/Drug Interactions, and to Facilitate Design of Clinical Trials

Species differences in drug metabolism and disposition can confound the extrapolation of in vivo pharmacokinetic data to man, and also profoundly compromise drug efficacy studies due to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active) and in differential activation of the transcription factors CAR and PXR which regulate the expression of enzymes such as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug efficacy testing and also patient-derived xenografts to predict individual patient responses to anti-cancer drugs. A number of humanised mouse models for cytochrome P450s, CAR and PXR have been reported. However, the utility of these models has been compromised as a consequence of the redundancy of P450 reactions across gene families where the remaining murine P450s can metabolise the compounds being tested. To remove this confounding factor and create a mouse model which more closely reflects human pathways of drug disposition we have substituted 33 murine P450s from the major gene families involved in drug disposition, together with Car and Pxr, for human CAR, PXR, CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP3A7. We have also created a mouse line where 34 P450s have been deleted from the mouse genome. We demonstrate using model compounds and anti-cancer drugs how these mouse lines can be applied to predict drug-drug interactions in patients and discuss their potential application in the more informed design of clinical trials and the personalised treatment of cancer.