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Lack of Interaction between Enfuvirtide and Ritonavir or Ritonavir-Boosted Saquinavir in HIV-1-Infected Patients

From the HIV Netherlands Australia Thailand Research Collaboration (HIVNAT), Thai Red Cross AIDS Research Centre, Pathumwan, Bangkok, Thailand (Dr. Ruxrungtham, Mr. Boyd); Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (Dr. Ruxrungtham); National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia (Mr. Boyd); Hoffmann-La Roche, Inc., Nutley, New Jersey (Dr. Bellibas, Dr. Zhang, Mr. Kolis, Dr. Kinchelow, Dr. Patel); XIQ Coordination, Inc., Fort Myers, Florida (Dr. Dorr); and F. Hoffmann-La Roche Ltd., Basel, Switzerland (Dr. Buss).

Enfuvirtide (Fuzeon^TM) is an HIV fusion inhibitor, the first drug in a new class of antiretrovirals. The HIV protease inhibitors ritonavir and saquinavir both inhibit cytochrome P450 (CYP450) isoenzymes, and low-dose ritonavir is often used to boost pharmacokinetic exposure to full-dose protease inhibitors. These two studies were designed to assess whether ritonavir and ritonavir-boosted saquinavir influence the steady-state pharmacokinetics of enfuvirtide. Both studies were single-center, open-label, one-sequence crossover clinical pharmacology studies in 12 HIV-1-infected patients each. Patients received enfuvirtide (90 mg twice daily [bid], subcutaneous injection) for 7 days and either ritonavir (200 mg bid, ritonavir study, orally) or saquinavir/ritonavir (1000/100 mg bid, saquinavir/ritonavir study, orally) for 4 days on days 4 to 7. Serial blood samples were collected up to 24 hours after the morning dose of enfuvirtide on days 3 and 7. Plasma concentrations for enfuvirtide, enfuvirtide metabolite, saquinavir, and ritonavir were measured using validated liquid chromatography tandem mass spectrometry methods. Efficacy and safety were also monitored. Bioequivalence criteria require the 90% confidence interval (CI) for the least squares means (LSM) of C_max and AUC_12h to be between 80% and 125%. In the present studies, analysis of variance showed that when coadministered with ritonavir, the ratio of LSM for enfuvirtide was 124% for C_max (90% confidence interval [CI]: 109%-141%), 122% for AUC_12h (90% CI: 108%-137%), and 114% for C_trough (90% CI: 102%-128%). Although the bioequivalence criteria were not met, the increase in enfuvirtide exposure was small (< 25%) and not clinically relevant. When administered with ritonavir-boosted saquinavir, the ratio of LSM for enfuvirtide was 107% for C_max (90% CI: 94.3%-121%) and 114% for AUC_12h (90% CI: 105%-124%), which therefore met bioequivalence criteria, and 126% for C_trough (90% CI: 117%-135%). The pharmacokinetics of enfuvirtide are affected to a small extent when coadministered with ritonavir at a dose of 200 mg bid but not when coadministered with a saquinavir-ritonavir combination (1000/100 mg bid). However, previous clinical studies have shown that such increases in enfuvirtide exposure are not clinically relevant. Thus, no dosage adjustments are warranted when enfuvirtide is coadministered with low-dose ritonavir or saquinavir boosted with a low dose of ritonavir.

Key Words: Enfuvirtide • T-20 • pharmacokinetics • drug-drug interaction • saquinavir • ritonavir

Address for reprints: Kiat Ruxrungtham, MD, Associate Professor of Medicine, Head Division of Allergy and Clinical Immunology, Department of Medicine, Chulalongkorn Hospital, and Deputy Director of HIV-NAT, Thai Red Cross AIDS Research Centre, Rama 4 Road, Bangkok 10330, Thailand.

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				H. Stocker, C. Kloft, N. Plock, A. Breske, G. Kruse, C. Herzmann, H. Schulbin, P. Kreckel, C. Weber, F. Goebel, et al. Pharmacokinetics of Enfuvirtide in Patients Treated in Typical Routine Clinical Settings Antimicrob. Agents Chemother., February 1, 2006; 50(2): 667 - 673. [Abstract] [Full Text] [PDF]