Effects of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes and an Inhibitor of OATP1B1/3 Transport, on the Single Dose Pharmacokinetics of Anacetrapib


  • M.S. Anderson, J. Cote, Y. Liu, A.O. Johnson-Levonas, and D. E. Gutstein are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. and may own stock or hold stock options in the company. D. Stypinski, P. Auger, A. Hohnstein, and S. Rasmussen are employees of Celerion, but report no conflicts of interest with regard to participation in this study.

Corresponding Author:

Matt S. Anderson, Clinical Pharmacology, Merck Sharp & Dohme Corp., 126 East Lincoln Avenue, Rahway, NJ 07065, USA

E-mail: matt.anderson@merck.com


Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0−∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.