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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.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2007 Apr; Vol. 51 (4), pp. 1202-8. Date of Electronic Publication: 2007 Jan 29. - Publication Year :
- 2007
-
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.
- Subjects :
- Adult
Area Under Curve
Benzodioxoles blood
Carbamates blood
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Combinations
Female
HIV Protease Inhibitors blood
HIV Protease Inhibitors pharmacokinetics
HIV-1 drug effects
Humans
Male
Middle Aged
Ritonavir administration & dosage
Ritonavir blood
Safety
Benzodioxoles adverse effects
Benzodioxoles pharmacokinetics
Carbamates adverse effects
Carbamates pharmacokinetics
HIV Infections drug therapy
HIV Protease Inhibitors adverse effects
HIV Protease Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0066-4804
- Volume :
- 51
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 17261626
- Full Text :
- https://doi.org/10.1128/AAC.01005-06