title: 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.affiliation: Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709, USA. sunila.y.reddy@gsk.com
authors.forename: Y Sunila
authors.initials: YS
authors.lastname: Reddy
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ford
authors.forename: Maggie T
authors.initials: MT
authors.lastname: Anderson
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Murray
authors.forename: Judith
authors.initials: J
authors.lastname: Ng-Cashin
authors.forename: Mark A
authors.initials: MA
authors.lastname: Johnson
mesh_terms: D000328:Adult; D019540:Area Under Curve; D052117:Benzodioxoles / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D002219:Carbamates / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood; D012449:Safety
chemical_list: D052117:Benzodioxoles; D002219:Carbamates; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; C512121:brecanavir; D019438:Ritonavir