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Antimicrobial Agents and Chemotherapy, July 2009, p. 2852-2856, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01468-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir{triangledown}

Larissa A. Wenning,1* William D. Hanley,1 Diana M. Brainard,1 Amelia S. Petry,1 Kalyan Ghosh,1 Bo Jin,1 Eric Mangin,1 Thomas C. Marbury,2 Jolene K. Berg,3 Jeffrey A. Chodakewitz,1 Julie A. Stone,1 Keith M. Gottesdiener,1 John A. Wagner,1 and Marian Iwamoto1

Merck & Co., Inc., Whitehouse Station, New Jersey,1 Orlando Clinical Research Center, Orlando, Florida,2 CEDRA Clinical Research, LLC, San Antonio, Texas3

Received 3 November 2008/ Returned for modification 22 February 2009/ Accepted 5 May 2009

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor that is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin (rifampicin). Two pharmacokinetic studies were performed in healthy subjects: study 1 examined the effect of administration of 600-mg rifampin once daily on the pharmacokinetics of a single dose of 400-mg raltegravir, and study 2 examined the effect of 600-mg rifampin once daily on the pharmacokinetics of 800-mg raltegravir twice daily compared to 400-mg raltegravir twice daily without rifampin. Raltegravir coadministered with rifampin resulted in lower plasma raltegravir concentrations: in study 1, the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the plasma raltegravir concentration determined 12 h postdose (C12), area under the concentration-time curve from 0 h to {infty} (AUC0-{infty}), and maximum concentration of drug in plasma (Cmax) (400-mg raltegravir plus rifampin/400-mg raltegravir) were 0.39 (0.30, 0.51), 0.60 (0.39, 0.91), and 0.62 (0.37, 1.04), respectively. In study 2, the GMRs and 90% CIs for raltegravir C12, AUC0-12, and Cmax (800-mg raltegravir plus rifampin/400-mg raltegravir) were 0.47 (0.36, 0.61), 1.27 (0.94, 1.71), and 1.62 (1.12, 2.33), respectively. Doubling the raltegravir dose to 800 mg when coadministered with rifampin therefore compensates for the effect of rifampin on raltegravir exposure (AUC0-12) but does not overcome the effect of rifampin on raltegravir trough concentrations (C12). Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used, since raltegravir trough concentrations in the presence of rifampin are likely to be at the lower limit of clinical experience.

* Corresponding author. Mailing address: Merck & Co., Inc., P.O. Box 4, West Point, PA 19486. Phone: (215) 652-4345. Fax: (215) 993-1265. E-mail: Larissa_Wenning{at}merck.com

{triangledown} Published ahead of print on 11 May 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2852-2856, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01468-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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