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Antimicrobial Agents and Chemotherapy, April 2007, p. 1202-1208, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01005-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Y. Sunila Reddy,* Susan L. Ford, Maggie T. Anderson, Sharon C. Murray, Judith Ng-Cashin, and Mark A. Johnson

GlaxoSmithKline, Research Triangle Park, North Carolina

Received 11 August 2006/ Returned for modification 25 September 2006/ Accepted 16 January 2007

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.

* Corresponding author. Mailing address: Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709. Phone: (919) 483-3714. Fax: (919) 315-4529. E-mail: sunila.y.reddy{at}gsk.com

{triangledown} Published ahead of print on 29 January 2007.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1202-1208, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01005-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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