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Antimicrob. Agents Chemother. doi:10.1128/AAC.00487-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Minimal Pharmacokinetic Interaction Between the HIV Non-Nucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Department of Clinical Pharmacology, Merck & Co., Inc., Whitehouse Station, NJ, USA; Tibotec Inc., Yardley, PA, USA; Tibotec BVBA, Mechelen, Belgium; Covance GFI Research, Evansville, IN, USA

^* To whom correspondence should be addressed. Email: matt_anderson{at}merck.com.

	Abstract

Etravirine, a next generation non-nucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced HIV-infected patients. An open-label, sequential 3-period study in healthy HIV-seronegative subjects was conducted to assess the 2-way interaction between etravirine and raltegravir for potential co-administration in HIV-infected patients. In Period 1, nineteen subjects were administered 400mg raltegravir q12 h for 4 days followed by a 4 day washout; in Period 2, subjects were administered 200mg etravirine q12 h for 8 days; and in Period 3, subjects were coadministered 400mg raltegravir and 200mg etravirine q12 hr 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 raltegravir pharmacokinetics while raltegravir had no clinically meaningful effect on etravirine pharmacokinetics. The geometric mean ratio (GMR) and 90% confidence interval (CI) for raltegravir co-administered with etravirine relative to raltegravir alone was 0.90 (0.68 to 1.18) for AUC_0-12h, 0.89 (0.68 to 1.15) for C_max, and 0.66 (0.34 to 1.26) for C_12h; the GMR (90% CI) for etravirine co-administered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC_0-12h, 1.04 (0.97, 1.12) for C_max, and 1.17 (1.10, 1.26) for C_12h. 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. Co-administration of etravirine and raltegravir was generally well tolerated; data suggest that no dose adjustment for either drug is necessary.