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 t1/2 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‐1HXB2 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.