Inhibition of In Vitro Metabolism of Simvastatin by Itraconazole in Humans and Prediction of In Vivo Drug-Drug Interactions

Purpose. To evaluate an interaction between simvastatin and itraconazole in in vitro studies and to attempt a quantitative prediction of in vivo interaction in humans. Methods. The inhibitory effect of itraconazole on simvastatin metabolism was evaluated using human liver microsomes and the K_i values were calculated for the unbound drug in the reaction mixture. A physiologically-based pharmacokinetic model was used to predict the maximum in vivo drug-drug interaction. Results. Itraconazole competitively inhibited the metabolism of simvastatin to M-1 and M-2 with K_i values in the nM range. The area under the curve (AUC) of simvastatin after concomitant dosing with itraconazole was predicted to increase ca. 84-101-fold compared with that without administration of itraconazole. Taking into consideration the fact that this method predicts the maximum interaction, this agrees well with the clinical observation of a 19-fold increase. A similar prediction, based on the K_i value without taking into account the drug adsorption to microsomes, led to an underevaluation of the interaction. Conclusions. It was demonstrated that the competitive inhibition of CYP3A4-mediated simvastatin metabolism by itraconazole is the main cause of the drug interaction and that a K_i value corrected for drug adsorption to microsomes is the key factor in quantitatively predicting the maximum in vivo drug interactions.