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 GW 420867X, a new nonnucleoside reverse transcriptase inhibitor, using a singl e escalating dose protocol in healthy volunteers. Four dose levels were inv estigated 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 t ime 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. Le ss than dose-proportional increases were observed for C-max. The terminal e limination 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. GW 420867X was generally well tolerated following single-dose administration u p to 900 mg; increased central nervous system-related adverse events were o bserved at higher doses. GW420867X had a favorable pharmacokinetic and safe ty profile that would enable this drug to be explored in future clinical st udies with HIV-1 infected patients at doses that would provide appropriate safety and efficacy. (C) 2001 the American College of Clinical Pharmacology .