Quantitative prediction of CYP2C9-mediated drug disposition using humanized mice

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Preclinical Drug Development
• Drug-Drug Interaction (DDI) Prediction

Background:

• Predicting drug clearance and DDIs, especially for low-clearance compounds, remains a challenge in drug development.
• Accurate prediction of in vivo fraction metabolized (fm) and DDI intensity is crucial for investigational drugs.

Purpose of the Study:

• To evaluate the utility of human liver chimeric mice (hu-PXB mice) in predicting CYP2C9-mediated drug disposition and DDIs for low-clearance compounds.
• To compare the predictive performance of hu-PXB mice against traditional SCID mice for human drug metabolism and DDI studies.

Main Methods:

• In vitro estimation of CYP2C9 fraction metabolized (fm,CYP2C9,in vitro) using human hepatocytes and a CYP2C9 inhibitor (sulfaphenazole).
• In vivo estimation of CYP2C9 fraction metabolized (fm,CYP2C9,in vivo) by analyzing clinical DDI data.
• Administration of CYP2C9 substrates (phenytoin, tolbutamide, warfarin) to hu-PXB and SCID mice with or without CYP2C9 inhibitors (sulfaphenazole, tienilic acid) to assess clearance changes.

Main Results:

• Hu-PXB mice showed a better correlation with human clinical data in terms of clearance changes and absolute values compared to SCID mice.
• Hu-PXB mice predicted CYP2C9-mediated DDI magnitude within 15% and substrate clearance within a 2-fold range of clinical values.
• In vitro fm,CYP2C9 values for phenytoin and tolbutamide were overestimated compared to in vivo estimates.

Conclusions:

• Hu-PXB mice serve as a reliable preclinical model for predicting human CYP2C9-mediated drug disposition and DDI magnitude.
• This model aids in selecting promising drug candidates and optimizing clinical trial designs for investigational drugs.