Pharmacokinetics and safety of escalating single and repeat oral doses of GW420867X, a novel non-nucleoside reverse transcriptase inhibitor

Objective: To assess the pharmacokinetics, safety and tolerability of escal ating oral doses of GW420867X, a non-nucleoside reverse transcriptase inhib itor, was investigated in healthy male volunteers in a randomized, double-b lind placebo-controlled study. Methods: Study subjects were divided into four groups of 12 subjects (10, 5 0, 100 and 200-mg dose groups) with eight subjects from each group receivin g active treatment and the remaining four matched placebo. Subjects were in itially administered a single dose of GW420867X or placebo, and following a 24- to 28-day washout period, re-exposed to the same treatment for 14 cons ecutive days. Safety measurements including clinical laboratory evaluations , ECG and vital signs were performed before, during and after dosing. Results. Geometric mean GW420867X peak plasma concentrations (C-max) follow ing single oral doses of 10, 50, 100 and 200 mg were 160, 608, 1000 and 166 2 ng/ml, respectively. Time to C-max (t(max)) increased from a median value of 1 h following the 10-mg dose, to 3 h after the 200-mg dose. Geometric m ean plasma areas under the curves (AUC) were 4325 (10 mg), 17,862 (50 mg), 35,295 (100 mg) and 62,338 ng/ml per hour (200 mg) and were proportionally less than the increase in the administered dose. Apparent terminal eliminat ion half-life (t(1/2)) was approximately 50 h. Following repeat dosing, acc umulation ratios based on plasma AUC were: 3.0 +/- 1.0 (10 mg), 2.6 +/- 0.9 (50 mg), 1.8 +/- 0.3 (100 mg) and 1.9 +/- 0.8 (200 mg) after 14 days of do sing compared to the corresponding single dose. In general, oral clearance (CL/F) was greater after 14 days and greater with higher doses except for t he 10-mg dose group. Steady-state CL/F was 2.2, 3.4, 4.2, and 5.1 1/h for 1 0, 50, 100, and 200 mg, respectively. Steady-state was generally achieved w ithin 7-10 days. Comparison of single and repeat dosing with GW420867X show ed that C-max increased by a factor of between 1.4 to 1.8, after 14 days of daily dosing to 288 (10 mg), 1006 (50 mg), 1401 (100 mg) and 2613 (200 mg) ng/ml. These increases were proportionally less than the increase in the a dministered dose. GW420867X was well tolerated by subjects both after singl e and repeated dosing. Adverse effects reported by subjects on the active d rug were similar to those receiving placebo. All episodes were rated as mil d to moderate in severity and resolved spontaneously without further interv ention. Conclusion: The pharmacokinetic findings of this study imply that systemic exposure to GW420867X decreases with increasing dose and displays time-vari ant pharmacokinetics, which suggests decreased absorption and/or increased clearance of GW420867X. The relatively long plasma half-life, of approximat ely 50 h, makes it suitable for once-daily dosing.