Use of a Physiologically Based Pharmacokinetic Model for Quantitative Prediction of Drug-Drug Interactions via CYP3A4 and Estimation of the Intestinal Availability of CYP3A4 Substrates

Abstract

The purpose of this study was to predict the drug-drug interactions (DDIs) via CYP3A4 by estimating the extent of hepatic CYP3A4 inhibition based on a physiologically based pharmacokinetic (PBPK) model of both substrate and inhibitor and the increase in the intestinal availability (Fg) due to the enzyme inhibition. For the DDIs resulting from reversible inhibition of CYP3A4, the prediction using in vivo Ki values estimated from other clinical DDI studies and predicted in vivo Ki values calculated using the correlation between the log P and the in vivo Ki/in vitro Ki ratio was more accurate than that using in vitro Ki values. Incorporating inhibition of both intestinal and hepatic metabolism resulted in better prediction than that obtained considering inhibition in the liver alone, and all the DDIs (AUC increase by the inhibitor) were predicted within 2-fold accuracy when in vivo Ki values were used. In addition, Fg values were successfully back-calculated from the clinical DDI data based on the present model. In conclusion, the present PBPK model incorporating the in vivo Ki values was found to be useful for quantitative prediction of clinical DDIs and for estimation of the Fg values for CYP3A4 substrates for which intravenous data were not available.