title: Single-dose safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus protease inhibitor.
abstract: Brecanavir (BCV, 640385) is a novel, potent protease inhibitor (PI) with low nanomolar 50% inhibitory concentrations against PI-resistant human immunodeficiency virus (HIV) in vitro. This phase I, double-blind, randomized, placebo-controlled, two-part single-dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of BCV administered at 10 mg/ml in a tocopherol-polyethylene glycol succinate-polyethylene glycol 400-ethanol 50:40:10 solution. In part 1 of the study, single oral doses of BCV ranged from 25 mg to 800 mg. In part 2, single oral doses of BCV ranged from 10 mg to 300 mg and were coadministered with 100-mg oral ritonavir (RTV) soft gel capsules. Single doses of BCV and BCV/RTV were generally well tolerated. There were no severe adverse events (SAEs), and no subject was withdrawn due to BCV. The most commonly reported drug-related AEs during both parts of the study combined were gastrointestinal disturbances (similar to placebo) and headache. BCV was readily absorbed following oral administration with mean times to maximum concentration from >1 h to 2.5 h in part 1 and from 1.5 h to 3 h in part 2. Administration of BCV without RTV resulted in BCV exposures predicted to be insufficient to inhibit PI-resistant virus based on in vitro data. Coadministration of 300 mg BCV with 100 mg RTV, however, significantly increased the plasma BCV area under the concentration-time curve and maximum concentration 26-fold and 11-fold, respectively, achieving BCV concentrations predicted to inhibit PI-resistant HIV.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA. susan.l.ford@gsk.com
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ford
authors.forename: Y Sunila
authors.initials: YS
authors.lastname: Reddy
authors.forename: Maggie T
authors.initials: MT
authors.lastname: Anderson
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Murray
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernandez
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Stein
authors.forename: Mark A
authors.initials: MA
authors.lastname: Johnson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002214:Capsules; D002219:Carbamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005414:Flatulence / Q000139:chemically induced; D005782:Gels; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood
chemical_list: D052117:Benzodioxoles; D002214:Capsules; D002219:Carbamates; D004338:Drug Combinations; D005782:Gels; D017320:HIV Protease Inhibitors; C512121:brecanavir; D019438:Ritonavir