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Antimicrobial Agents and Chemotherapy, December 2008, p. 4338-4343, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.01543-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Minimal Effects of Ritonavir and Efavirenz on the Pharmacokinetics of Raltegravir

Merck & Co., Inc., Whitehouse Station, New Jersey,¹ Thomas Jefferson University, Philadelphia, Pennsylvania,² SGS Life Sciences Services, Antwerp, Belgium³

Received 29 November 2007/ Returned for modification 5 April 2008/ Accepted 28 September 2008

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C_{12 h}) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC_0-) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C_max) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C_{12 h} GMR (90% CI) was 0.79 (0.49, 1.28); AUC_0- was 0.64 (0.52, 0.80); and C_max was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.

Published ahead of print on 6 October 2008.