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Antimicrobial Agents and Chemotherapy, June 2006, p. 2201-2206, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.01490-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Single-Dose Safety and Pharmacokinetics of Brecanavir, a Novel Human Immunodeficiency Virus Protease Inhibitor

Susan L. Ford,1* Y. Sunila Reddy,1 Maggie T. Anderson,1 Sharon C. Murray,1 Pedro Fernandez,1 Daniel S. Stein,2 and Mark A. Johnson1

GlaxoSmithKline, Research Triangle Park, North Carolina,1 Sanofi-Aventis Pharmaceuticals, Bridgewater, New Jersey2

Received 18 November 2005/ Returned for modification 21 January 2006/ Accepted 24 March 2006

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 There were no severe adverse events (SAEs), and no subject was withdrawn due to BCV.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.

* Corresponding author. Mailing address: Division of Clinical Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC 27709. Phone: (919) 483-0392. Fax: (919) 483-6380. E-mail: susan.l.ford{at}gsk.com.

Antimicrobial Agents and Chemotherapy, June 2006, p. 2201-2206, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.01490-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hazen, R., Harvey, R., Ferris, R., Craig, C., Yates, P., Griffin, P., Miller, J., Kaldor, I., Ray, J., Samano, V., Furfine, E., Spaltenstein, A., Hale, M., Tung, R., St. Clair, M., Hanlon, M., Boone, L. (2007). In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV. Antimicrob. Agents Chemother. 51: 3147-3154 [Abstract] [Full Text]  
  • Lalezari, J. P., Ward, D. J., Tomkins, S. A., Garges, H. P. (2007). Preliminary safety and efficacy data of brecanavir, a novel HIV-1 protease inhibitor: 24 week data from study HPR10006. J Antimicrob Chemother 60: 170-174 [Abstract] [Full Text]  
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