Pharmacokinetic properties and tolerability of bevirimat and atazanavir in healthy volunteers: An open-label, parallel-group study

• Published in: Clinical therapeutics 2008-10, Vol.30 (10), p.1794-1805
• Main Authors: Martin, David E., PharmD, MBA, Galbraith, Hal, PharmD, Schettler, Jared, MS, Ellis, Corey, MS, Doto, Judy, BSN
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - pharmacokinetics; Area Under Curve; atazanavir; Atazanavir Sulfate; bevirimat; Biological and medical sciences; Body Mass Index; Drug Interactions; Drug Therapy, Combination; Female; Half-Life; Humans; interaction; Internal Medicine; Male; Medical Education; Medical sciences; Middle Aged; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Oligopeptides - pharmacokinetics; pharmacokinetic; Pharmacology. Drug treatments; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - pharmacokinetics; Succinates - administration & dosage; Succinates - adverse effects; Succinates - pharmacokinetics; tolerability; Triterpenes - administration & dosage; Triterpenes - adverse effects; Triterpenes - pharmacokinetics; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2008.10.006

Abstract Background: Bevirimat, an inhibitor of HIV-1 maturation, is currently in clinical development for the treatment of HIV-1 infection. It undergoes glucuronidation via uridine diphosphate glucuronosyltransferases (UGTs). The protease inhibitor atazanavir is a potent inhibitor of UGT1A1. Because of this inhibition, high atazanavir plasma levels are associated with increases in plasma bilirubin. Objectives: The purposes of this study were to assess the pharmacokinetic (PK) properties and tolerability profiles of bevirimat administered as monotherapy and in combination with atazanavir. Methods: This was an open-label, parallel-group study in healthy volunteers. Nonsmoking men and women aged 18 to 60 years were eligible for inclusion in the study. After being stratified in a 1:1 ratio by sex, subjects were randomly assigned to 1 of 2 groups to receive bevirimat 200 mg/d for 14 days or atazanavir 400 mg/d on days 1 through 21 and bevirimat 200 mg/d on days 8 through 21. Bevirimat PK properties were assessed on day 14 in the monotherapy group and on day 21 in the combination group. Atazanivir PK properties were assessed on days 7 and 21 in the combination group. Serum bilirubin was assessed daily. Tolerability was assessed by monitoring of adverse events using physical examination and clinical laboratory evaluation, including recording of vital signs and electrocardiography throughout the study. Results: A total of 48 healthy volunteers (24 men, 24 women; mean age, 33 years; mean weight, 83.6 kg; mean body mass index, 27.8 kg/m2 ) were included in the study. There were no significant between-group effects on the PK properties with respect to geometric least squares mean ratios of Cmax and AUC0–τ (95.9 [90% CI, 84.5–108.8] and 92.0 [90% CI, 80.5– 105.2], bevirimat monotherapy vs bevirimat + atazanivir, respectively; and 93.9 [90% CI, 82.3–107.1 and 94.1 [90% CI, 78.2–113.1], atazanivir monotherapy vs bevirimat + atazanivir, respectively). Bevirimat was not associated with any significant changes from baseline in serum bilirubin concentrations, whereas 7-day atazanavir monotherapy was associated with a ~5-fold increase. Coadministration was not associated with significant bilirubin concentration elevations compared with the administration of atazanavir alone. Dosing was discontinued in 4 subjects (atazanavir-induced hyperbilirubinemia, 3; atazanavir-induced rash, 1). In addition, 17 subjects (35.4%) experienced treatment-emergent adverse events including: oc