Received for publication March 11, 2008.
Revised April 26, 2008.
Accepted for publication April 28, 2008.

Effects of ketoconazole and quinidine on pharmacokinetics of pactimibe and its plasma metabolite, R-125528, in human

Abstract

Pactimibe sulfate is a novel Acyl coenzyme A: cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is solely cleared by CYP2D6 in spite of its acidity. To evaluate contribution of the P450 enzymes on pharmacokinetics of pactimibe and R-125528 in humans, DDI studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were received a single dose of pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, AUC_0-inf of pactimibe modestly increased 1.7-fold and AUC_0-tz of R-125528 decreased by 55%. Besides, seventeen healthy male subjects were received a single dose of pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, AUC_0-inf for pactimibe modestly increased 1.7-fold. On the other hand, AUC_0-tz of R-125528 was markedly elevated 5.0-fold, although AUC_0-inf could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 hr. As f_mCYP3A4 and f_mCYP2D6 of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, f_mCYP2D6 of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed in the quinidine treatment.

Key words: CYP2D, CYP3A, drug-drug interactions, genetic polymorphism