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Antimicrobial Agents and Chemotherapy, July 2009, p. 2752-2755, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01486-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effect of Tipranavir-Ritonavir on Pharmacokinetics of Raltegravir{triangledown}

William D. Hanley,1* Larissa A. Wenning,1 Allison Moreau,1 James T. Kost,1 Eric Mangin,1 Trisha Shamp,2 Julie A. Stone,1 Keith M. Gottesdiener,1 John A. Wagner,1 and Marian Iwamoto1

Merck & Co., Inc., Whitehouse Station, New Jersey,1 Prism Research, St. Paul, Minnesota2

Received 6 November 2008/ Returned for modification 31 January 2009/ Accepted 19 April 2009

Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (C12) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66; P = 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19; P = 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46; P = 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL C12 was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.

* Corresponding author. Mailing address: Merck & Co., Inc., P.O. Box 4, West Point, PA 19486. Phone: (215) 652-1052. Fax: (215) 993-1265. E-mail: william_hanley{at}merck.com

{triangledown} Published ahead of print on 27 April 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2752-2755, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01486-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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