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Lack of Interaction between Enfuvirtide and Ritonavir or Ritonavir‐Boosted Saquinavir in HIV‐1‐Infected Patients
Author(s) -
Ruxrungtham Kiat,
Boyd Mark,
Bellibas S. Eralp,
Zhang Xiaoping,
Dorr Albert,
Kolis Stanley,
Kinchelow Tosca,
Buss Neil,
Patel Indravadan H.
Publication year - 2004
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270004266489
Subject(s) - saquinavir , enfuvirtide , ritonavir , pharmacology , pharmacokinetics , bioequivalence , medicine , crossover study , protease inhibitor (pharmacology) , virology , viral load , human immunodeficiency virus (hiv) , gp41 , immunology , alternative medicine , pathology , antigen , epitope , placebo , antiretroviral therapy
Enfuvirtide (Fuzeon™) 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.