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Antimicrobial Agents and Chemotherapy, January 2004, p. 116-123, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.116-123.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Six-Week Randomized Controlled Trial To Compare the Tolerabilities, Pharmacokinetics, and Antiviral Activities of GW433908 and Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients

Robin Wood,¹ Keikawus Arasteh,² Hans-Jürgen Stellbrink,³ Eugenio Teofilo,⁴ François Raffi,⁵ Richard B. Pollard,⁶ Joseph Eron,⁷ Jane Yeo,⁸ Judith Millard,⁹ Mary Beth Wire,¹⁰ and Odin J. Naderer^10*

Somerset Hospital, University of Cape Town, Cape Town, South Africa,¹ Epimed GmbH, Auguste-Victoria-Krankenhaus, Berlin,² Universitaetsklinikum Eppendorf, Hamburg, Germany,³ Servico de Medicina 3, Lisbon, Portugal,⁴ CHRU de Nantes, Nantes, France,⁵ University of California—Davis, Sacramento, California,⁶ University of North Carolina at Chapel Hill, Chapel Hill,⁷ HIV Clinical Development and Medical Affairs,⁹ Clinical Pharmacology Discovery Medicine, GlaxoSmithKline, Research Triangle Park, North Carolina,¹⁰ HIV Clinical Development and Medical Affairs, GlaxoSmithKline, Greenford, Middlesex, United Kingdom⁸

Received 20 February 2003/ Returned for modification 8 May 2003/ Accepted 18 September 2003

This study compared the plasma amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors amprenavir (Agenerase) 1,200 mg twice daily (BID) and the amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma amprenavir concentration-time curve (AUC) at the end of a dosing interval (), lower maximum plasma amprenavir concentrations (30% lower), and higher plasma amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma amprenavir pharmacokinetics were observed with reductions in plasma amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma amprenavir AUC_,ss versus the AUC from 0 h to was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA (2 log₁₀ copies/ml) and increased CD4⁺ cell counts (100 cells/mm³) over the initial 28 days. Adverse event profiles were consistent with those previously reported for amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma amprenavir concentrations to those delivered by amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.

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* Corresponding author. Mailing address: Clinical Pharmacology Discovery Medicine, GlaxoSmithKline, 5 Moore Dr., P.O. Box 13398, Research Triangle Park, NC 27709. Phone: (919) 483-1882. Fax: (919) 483-6380. E-mail: ojn98495{at}gsk.com.

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Antimicrobial Agents and Chemotherapy, January 2004, p. 116-123, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.116-123.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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