GW420867X administered to HIV-1-infected patients alone and in combination with lamivudine and zidovudine.

Author(s): Arasteh K, Wood R, Muller M, Prince W, Cass L, Moore KH, Dallow N, Jones A, Klein A, Burt V, Kleim JP

Affiliation(s): EPIMED-Auguste-Viktoria-Hospital, Berlin, Germany. arasteh@avk.b.shuttle.de

Publication date & source: 2001-07, HIV Clin Trials., 2(4):307-16.

Publication type: Clinical Trial; Randomized Controlled Trial

PURPOSE: GW420867X is a nonnucleoside inhibitor of HIV-1 reverse transcriptase. The primary objective was to assess the safety of GW420867X in HIV-1-infected patients. The secondary objectives were to assess the effect of GW420867X on plasma HIV-1 RNA and viral genotype and phenotype and to examine the pharmacokinetics of GW420867X in HIV-1-infected patients. METHOD: HIV-1-infected patients were randomized to GW420867X 50 mg/day, 100 mg/day, or 200 mg/day from days 1-28 (n = 15 per group). Lamivudine (3TC) plus zidovudine (ZDV) was added from days 8-28. A control group (n = 15) received GW420867X, 3TC, and ZDV placebos. RESULTS: Plasma HIV-1 RNA and CD4+ counts improved in the GW420867X groups at days 8 and 28. No significant development of drug resistance was detected. Median observed peak GW420867X concentration (C(max)) generally occurred at 2 hours. The area under the curve over the dosing interval (AUCtau)on day 14 increased less than proportionally to dose, suggesting there was increased clearance and/or decreased absorption. Mean trough GW420867X concentrations were many fold above the in vitro IC(50) in the presence of human serum proteins. Seven of 15 patients on 50 mg GW420867X, 8/15 on 100 mg GW420867X, 12/15 on 200 mg GW420867X, and 8/15 on placebo reported drug-related adverse events. CONCLUSION: GW420867X was well tolerated and has potent antiretroviral activity alone and in combination with 3TC plus ZDV.