Inhibition of In Vitro Metabolism of Simvastatin by Itraconazole in Humans and Prediction of In Vivo Drug-Drug Interactions |
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Authors: | Ishigam Michi Uchiyama Minoru Kondo Tomoko Iwabuchi Haruo Inoue Shin-ichi Takasaki Wataru Ikeda Toshihiko Komai Toru Ito Kiyomi Sugiyama Yuichi |
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Affiliation: | (1) Drug Metabolism and Pharmacokinetics Research Laboratories and Product Strategy Department, Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan;(2) School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan;(3) Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan;(4) 3-1,7-Chome, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan |
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Abstract: | 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 Ki 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 Ki 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 Ki 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 Ki value corrected for drug adsorption to microsomes is the key factor in quantitatively predicting the maximum in vivo drug interactions. |
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Keywords: | drug-drug interaction CYP3A4 HMG-CoA reductase inhibitor simvastatin pravastatin itraconazole |
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