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

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.