Hanley WD, Wenning LA, Moreau A, Kost JT, Mangin E, Shamp T, Stone JA, Gottesdiener KM, Wagner JA, Iwamoto M
Effect of Tipranavir + Ritonavir on Pharmacokinetics of Raltegravir. [JOURNAL ARTICLE]
Antimicrob Agents Chemother 2009 Apr 27.
Raltegravir (RAL) is a novel and potent HIV-1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir 500 mg with ritonavir 200 mg (TPV+RTV) has inhibitory and inductive effects on metabolic enzymes, including potential induction of glucuronosyltransferase. Because RAL may be coadministered with TPV+RTV, there is the potential for induction of RAL metabolism. Consequently, we assessed the effect of TPV+RTV on RAL pharmacokinetics and the safety and tolerability of this combination. In this open-label study, 18 healthy adults were enrolled. Participants received RAL 400 mg twice daily for 4 days (Period 1), TPV+RTV twice daily for 7 days (Period 2), followed immediately by RAL 400 mg with TPV+RTV twice daily for 4 days (Period 3). Under steady-state conditions, RAL C12hr was decreased when RAL was administered with TPV+RTV (GMR =0.45 [90% CI: 0.31, 0.66] (p=0.0021)); however, AUC0-12 hr GMR (0.76 [0.49, 1.19] (p=0.2997)) and Cmax (0.82 [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 raltegravir coadministered with TPV+RTV was generally well tolerated. Although RAL C12hr 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.
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