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Antimicrobial Agents and Chemotherapy, December 2008, p. 4228-4232, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00487-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Department of Clinical Pharmacology, Merck & Co., Inc., Whitehouse Station, New Jersey,¹ Tibotec Inc., Yardley, Pennsylvania,² Tibotec BVBA, Mechelen, Belgium,³ Covance GFI Research, Evansville, Indiana⁴

Received 14 April 2008/ Returned for modification 2 August 2008/ Accepted 28 September 2008

Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC_0-12), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (C_max), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C₁₂); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC_0-12, 1.04 (0.97, 1.12) for C_max, and 1.17 (1.10, 1.26) for C₁₂. All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.

Published ahead of print on 6 October 2008.