J Clin Pharmacol
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0091270008326718v1
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DRUG INTERACTIONS

Assessment of the CYP3A-Mediated Drug Interaction Potential of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Volunteers

Rajesh Krishna, PhD, FCP, Arthur J. Bergman, PhD, Bo Jin, PhD, Amit Garg, PhD, Brad Roadcap, MS, Rita Chiou, MS, James Dru, MS, Josee Cote, BS, Tine Laethem, PhD, Regina W. Wang, MS, Varsha Didolkar, MS, Eva Vets, MD, Keith Gottesdiener, MD and John A. Wagner, MD, PhD

From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Krishna, Dr Bergman, Dr Jin, Dr Garg, Dr Roadcap, Ms Chiou, Mr Dru, Ms Cote, Dr Laethem, Dr Wang, Dr Didolkar, Dr Gottesdiener, Dr Wagner) and SGS Biopharma, Antwerp, Belgium (Dr Vets).

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probeinhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-{infty} and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole—specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-{infty} and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.

Key Words: CETP inhibition • CYP3A • ketoconazole • midazolam

Address for reprints: Rajesh Krishna, PhD, FCP, Merck Research Laboratories, Mailstop RY34-A500, 126 East Lincoln Avenue, Rahway, NJ 07065-0900; e-mail: rajesh_krishna{at}merck.com.


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