Safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus type 1 protease inhibitor, following repeat administration with and without ritonavir in healthy adult subjects.

Abstract

Brecanavir (BCV) is a novel, potent protease inhibitor in development for the treatment of human immunodeficiency virus (HIV-1) infection with low nM in vitro 50% inhibitory concentrations (IC50s) against many multiprotease inhibitor resistant viruses. This study was a double-blind, randomized, placebo-controlled repeat-dose escalation to evaluate the safety, tolerability, and pharmacokinetics of BCV, with or without ritonavir (RTV), in 68 healthy subjects. Seven sequential cohorts (n=10) received BCV (50 to 600 mg) in combination with 100 mg RTV (every 12 h [q12h] or q24h) or alone at 800 mg q12h for 15 days. BCV alone or in combination with RTV was well tolerated, with no serious adverse events reported. The most common drug-related adverse event was headache. BCV was readily absorbed with median time to maximum concentration of drug in serum values ranging from 2.5 to 5.0 h postdose following single- and repeat-dose administration of BCV alone and BCV with RTV 100 mg. Geometric mean BCV accumulation ratios ranged from 1.4 to 1.56 following BCV-RTV q24h regimens and from 1.84 to 4.93 following BCV q12h regimens. BCV steady state was generally achieved by day 13 in all groups. All day 15 BCV-RTV trough concentration values in q12h regimens reached or surpassed the estimated protein-binding corrected in vitro IC50 target BCV concentration of 28 ng/ml for highly resistant isolates. The pharmacokinetic and safety profile of BCV-RTV supports continued investigation in HIV-1-infected subjects.

• Authors: Y Sunila Reddy, Susan L Ford, Maggie T Anderson, Sharon C Murray, Judith Ng-Cashin, Mark A Johnson
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 51 Issue 4 Pg. 1202-8 (Apr 2007) ISSN: 0066-4804 [Print] United States
• PMID: 17261626 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Benzodioxoles
• Carbamates
• Drug Combinations
• HIV Protease Inhibitors
• brecanavir
• Ritonavir

Topics

• Adult
• Area Under Curve
• Benzodioxoles (adverse effects, blood, pharmacokinetics)
• Carbamates (adverse effects, blood, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Combinations
• Female
• HIV Infections (drug therapy)
• HIV Protease Inhibitors (adverse effects, blood, pharmacokinetics, therapeutic use)
• HIV-1 (drug effects)
• Humans
• Male
• Middle Aged
• Ritonavir (administration & dosage, blood)
• Safety