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Effect of Diltiazem, a Moderate CYP3A Inhibitor, on the Pharmacokinetics of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein Inhibitor, in Healthy Subjects

A (MK-0859) is a potent and selective inhibitor of cholesteryl ester transfer protein (CETP) currently undergoing development as an oral drug for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. A midazolam probe study demonstrated that anacetrapib neither induces nor inhibits CYP3A activity. A drug interaction study performed with ketoconazole as a potent CYP3A inhibitor suggested that anacetrapib is a moderately sensitive CYP3A substrate. Specifically, the exposure to anacetrapib was increased by ketoconazole; the geometric mean ratio (anacetrapib with ketoconazole/anacetrapib alone) for area under the plasma concentration vs. time curve from zero to infinity (AUC0-∞) and peak maximal concentration (Cmax) were 4.58 and 2.37 with 90% confidence interval of 3.68 to 5.71 and 2.02 to 2.78, respectively. Because a number of cardiovascular drugs widely used for the treatment of dyslipidemia are moderate CYP3A inhibitors, it is of interest to understand whether the interaction with diltiazem, a probe moderate CYP3A inhibitor, will be clinically meaningful. Therefore, the effect of diltiazem, a moderate CYP3A inhibitor, on the pharmacokinetic parameters of anacetrapib was studied. Specifically, the goal of this study was to establish that the concomitant use of moderate CYP3A4 inhibitors does not alter the pharmacokinetic and safety profile of anacetrapib to a clinically meaningful extent.