Pharmacokinetics and tolerability of GW420867X, a nonnucleoside reverse transcriptase inhibitor, following single escalating doses in healthy male volunteers.

The aim of the current study was to characterize the pharmacokinetics of GW420867X, a new nonnucleoside reverse transcriptase inhibitor, using a single escalating dose protocol in healthy volunteers. Four dose levels were investigated in sequential order: 300, 600, 900, and 1200 mg, with a ratio of 4:1 subjects receiving active or placebo treatment, respectively. Following single-dose administration, GW420867X was readily absorbed with a median time to peak concentration of 3 to 5 hours. GW420867X plasma exposure (AUC) was dose proportional but variable within the 300 to 1200 mg dose range. Less than dose-proportional increases were observed for Cmax. The terminal elimination t(1/2) was 50 hours, which supports once-daily dosing in future studies. Plasma trough concentrations of GW420867X at 24 hours after dosing were many fold greater than the in vitro IC50 HIV-1(HXB2) in MT4 cells. GW420867X was generally well tolerated following single-dose administration up to 900 mg; increased central nervous system-related adverse events were observed at higher doses. GW420867X had a favorable pharmacokinetic and safety profile that would enable this drug to be explored in future clinical studies with HIV-1 infected patients at doses that would provide appropriate safety and efficacy.