Projections of Drug-Drug Interactions Caused by Time-Dependent Inhibitors of Cytochrome P450 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 Using In Vitro Data in Static and Dynamic Models

In vitro time-dependent inhibition (TDI) kinetic parameters for cytochrome P450 (P450) 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 were determined in pooled human liver microsomes for 19 drugs (and two metabolites) for which clinical drug-drug interactions (DDIs) are known. In vitro TDI data were incorporated into the projection of the magnitude of DDIs using mechanistic static models and Simcyp. Results suggest that for the mechanistic static model, use of estimated average unbound exit concentration of the inhibitor from the liver resulted in a successful prediction of observed magnitude of clinical DDIs and was similar to Simcyp. Overall, predictions of DDI magnitude (i.e., fold increase in AUC of a P450-specific marker substrate) were within 2-fold of actual values. Geometric mean fold errors were 1.7 and 1.6 for static and dynamic models, respectively. Projections of DDIs from both models were also highly correlated to each other (r2 = 0.92). This investigation demonstrates that DDIs can be reliably predicted from in vitro TDI data generated in human liver microsomes for several P450 enzymes. Simple mechanistic static model equations as well as more complex dynamic physiologically based pharmacokinetic models can be employed in this process.

SIGNIFICANCE STATEMENT

Cytochrome P450 time-dependent inhibitors (TDIs) can cause drug-drug interactions (DDIs). An ability to reliably assess the potential for a new drug candidate to cause DDIs is essential during drug development. In this report, TDI data for 19 drugs (and two metabolites) were measured and used in static and dynamic models to reliably project the magnitude of DDIs resulting from inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.