Pharmacokinetics of the New Antiepileptic and CNS Drug RWJ-333369 Following Single and Multiple Dosing to Humans

Summary: Purpose: To characterize the pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple oral doses to healthy subjects, including the effect of food on bioavailability.

Method: Two studies were conducted. The first study had a randomized, double-blind, placebo-controlled, sequential, ascending-dose crossover design. Subjects were divided into four dose groups (100, 250, 500, and 750 mg) of 10 to 11 subjects each. RWJ-333369 or placebo was administered for two 7-day periods, separated by a 14-day washout. In the second study RWJ-333369 (750 mg) was administered to 12 healthy subjects under fasted and fed conditions. Plasma and urine samples were analyzed for RWJ-333369 by liquid chromatography-mass spectroscopy. Safety was assessed throughout the studies.

Results: Mean (range) pharmacokinetic parameters in the above studies were: oral clearance (CL/F) 3.4–4.2 L/h, half-life (t_1/2) 10.6–12.8 h, and renal clearance (CLr) 0.042–0.094 L/h, indicating that RWJ-333369 is eliminated primarily by metabolism. These parameters were not significantly different (p > 0.05) for the four dose groups and for single and multiple dosing. C_max and AUC increased proportionally with dose and decreased with food by 11% and 5%, respectively.

Conclusions: Following single and repetitive (q12h) doses of 100–750 mg, RWJ-333369 had linear pharmacokinetics; food did not alter pharmacokinetics to a clinically relevant extent. RWJ-333369 is extensively metabolized and has a low CL/F that equals < 5% of the liver blood flow. Thus, orally administered RWJ-333369 has no hepatic first-pass effect. The 12-h half-life will enable bid dosing with an immediate-release oral formulation.