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

Abstract

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 (tau), 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(tau,ss) versus the AUC from 0 h to infinity 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 ( approximately 2 log(10) copies/ml) and increased CD4(+) cell counts ( approximately 100 cells/mm(3)) 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.

FIG. 1.

Summary of patient disposition in treatment periods 1 and 2.

FIG. 2.

Median steady-state plasma APV concentration-time profiles for the 908 1,395-mg BID (♦; n = 22), 908 1,860-mg BID (▪; n = 31), and APV 1,200-mg (▴; n = 53) groups at the end of treatment period 1 (day 28).

FIG. 3.

Percent change in plasma APV AUC versus percent change in AUC (day 28/day1).

FIG. 4.

Median plasma HIV-1 RNA changes from baseline for the 908 1,395-mg (♦), 908 1,860-mg (▪), and APV 1,200-mg (▴) groups in treatment period 1.