Inhibition of in vitro metabolism of simvastatin by itraconazole in humansand 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 inter action in humans. Methods. The inhibitory effect of itraconazole on simvastatin metabolism wa s evaluated using human liver microsomes and the K-i values were calculated for the unbound drug in the reaction mixture. A physiologically-based phar macokinetic model was used to predict the maximum in vivo drug-drug interac tion. 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 predicte d 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 tak ing into account the drug adsorption to microsomes, led to an underevaluati on of the interaction. Conclusions, It was demonstrated that the competitive inhibition of CYP3A4- mediated simvastatin metabolism by itraconazole is the main cause of the dr ug interaction and that a K-i value corrected for drug adsorption to micros omes is the key factor in quantitatively predicting the maximum in vivo dru g interactions.