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The purpose of this study was to investigate the potential for a CYP3A4‐mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15‐mg oral dose of MDZ with and without R667 coadministration. Serial blood samples were collected predose and up to 24 hours after each MDZ dose for pharmacokinetic (PK) evaluation. The PK parameters for MDZ, R667, and metabolites were estimated using noncompartmental methods. MDZ exposure was very similar in the presence and absence of R667 (Cmax= 50.8 vs 46.2 ng/mL; AUC0‐last= 215 vs 216 ng•h/mL; AUC0‐lastratio = 0.26 vs 0.26, respectively). R667 exposure was not affected by midazolam coadministration as compared with historical data. Based on the results of this study, no significant pharmacokinetic interaction should be anticipated between R667 and CYP3A4 substrates.

Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors.

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 Cmaxand AUC12hto 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 Cmax(90% confidence interval [CI]: 109%‐141%), 122% for AUC12h(90% CI: 108%‐137%), and 114% for Ctrough(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 Cmax(90% CI: 94.3%‐121%) and 114% for AUC12h(90% CI: 105%‐124%), which therefore met bioequivalence criteria, and 126% for Ctrough(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.

Introduction: Enfuvirtide is the first drug to block human immunodeficiency virus type 1 (HIV-1) glycoprotein 41–mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV-1–infected patients.Methods: An open-label, 1-sequence crossover study was conducted in 12 HIV-1–infected adults, by use of a 5-drug cocktail consisting of caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin to assess the activities of CYP1A2, CYP2E1, CYP3A4, CYP2D6, and CYP2C19, respectively. Dapsone was used to assess N-acetyltransferase activity. Patients received a single dose of the cocktail alone on day −15 and another together with enfuvirtide on day 6. Enfuvirtide (90 mg subcutaneously) was administered twice daily on days 1 to 7. Phenotypic index parameters were estimated and analyzed by ANOVA with factors subject and day (−15 and 6).Results: The phenotypic index parameters, with and without enfuvirtide, for CYP3A4 (0.33 versus 0.34; 90% confidence interval [CI] for ratio of least squares means, 0.88-1.09), CYP2D6 (0.72 versus 0.71; 90% CI, 0.97-1.06), and N-acetyltransferase (0.35 versus 0.39; 90% CI, 0.82-0.98) were bioequivalent. The phenotypic index parameters, with and without enfuvirtide, for CYP1A2 (0.76 versus 0.81; 90% CI, 0.71-1.17), CYP2E1 (1.3 versus 1.2; 90% CI, 0.87-1.29), and CYP2C19 (93 versus 81.8; 90% CI, 0.98-1.28) were not bioequivalent but were not substantially different.Conclusions: Enfuvirtide had no clinically important effect on the metabolism of probe drugs mediated by CYP3A4, CYP2D6, or N-acetyltransferase and had little effect on the metabolism of drugs mediated by CYP1A2, CYP2E1, or CYP2C19. The potential for interactions between enfuvirtide and concomitantly administered drugs metabolized by the CYP enzymes tested in this study is low.Clinical Pharmacology & Therapeutics (2004) 75, 558–568; doi: 10.1016/j.clpt.2004.02.003

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV‐1‐infected patients. In a single‐center, open‐label, one‐sequence crossover, clinical pharmacology study, 12 HIV‐1‐infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log‐transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady‐state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctroughfor enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short‐term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10‐day pretreatment with rifampicin.

Objective: Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies.Methods: Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method.Results: Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (±SD) were volume of distribution of the central compartment (3.8 ± 0.8 L), volume of distribution of the peripheral compartment (1.7 ± 0.6 L), total clearance (1.44 ± 0.30 L/h), intercompartmental distribution (2.3 ± 1.1 L/h), bioavailability (89% ± 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35hours for the subcutaneous dose range from 45 to 180 mg.Conclusions: An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.

The biotransformation of bromazepam, 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one, was studied in four species. Four metabolites were identified and their excretion was quantitatively determined. The major urinary metabolites excreted by three women given single 12-mg. oral doses of bromazepam-5-14C were the conjugated forms of 3-hydroxybromazepam (I), accounting for 13–30% of the dose, and 2-(2-amino-5-bromo-3-hydroxybenzoyl)pyridine (IV), accounting for 4–25% of the dose. Conjugated I was also the major metabolite in three dogs and four groups of mice administered 14C-bromazepam, but its excretion by four rats was very limited. Together with I, Metabolite IV and 2-(2-amino-5-bromobenzoyl)pyridine were detected in the excreta of the human, dog, rat, and mouse. Although the pyridyl N-oxide derivative of bromazepam was not detected as a metabolite in any species, the N4-oxide was aminor metabolite in dog urine. This is the first reported instance of metabolic N4-oxidation of a 1,4-benzodiazepin-2-one.