Abstracts

To assess the pharmacokinetics (PK), safety, and tolerability of RWJ-333369, a novel neuromodulator in clinical development for the treatment of epilepsy, after single and multiple administrations in healthy men over a wide range of doses. Two single-center, placebo-controlled, double-blind, ascending-dose studies were conducted in healthy men [ge]18 and [le]45 yrs. In study 1 (N=70), subjects were randomly assigned to one of 7 RWJ-333369 dose groups (100, 250, 400, 750, 1000, 1250, or 1500 mg active [n=49]) or placebo (n=21); all subjects received a single dose. PK parameters were estimated from plasma samples collected up to 2 days postdose. Study 2 (N=53) evaluated the PK and safety of repeated doses of RWJ-333369 in 4 dose groups (100, 250, 500, or 750 mg [n= 12 per dose group, 6 study drug, 6 placebo]). Within each group, subjects were assigned to q12h treatment for 1 wk and were crossed over after a 14 day washout period. PK parameters were estimated from plasma and urine samples on days 1 and 7. Study 1[italic]- Single dose: [/italic]RWJ-333369 was rapidly absorbed following oral administration. C[sub]max [/sub]and AUC[sub]0-[infin][/sub] increased in proportion to dose over the range of 100-1500 mg. Mean t[sub]max[/sub] ranged from 1.3-2.7 h. Mean t[sub]1/2[/sub] (11.5 - 13.9 h), CL/F (2.87-3.67 L/h), and Vd/F (52.1-66.2 L) values were similar for all 7 dose groups.
Study 2 -[italic]Repeated doses: [/italic]Plasma concentrations of RWJ-333369 reached steady state after 3-4 days as predicted from its single-dose half-life. Mean t[sub]max[/sub] occurred 1.3-1.8 h after dosing. The mean t[sub]1/2[/sub] (11.9-12.8 h) and CL/F (3.40-3.78 L/h) values at steady state were comparable to the PK parameters following single-dose administration on day 1 and in study 1. Steady-state C[sub]max [/sub]and AUC[sub]0-12[/sub] increased in proportion to the dose. RWJ-333369 C[sub]max[/sub] and AUC[sub]0-12[/sub] were about two-fold higher on day 7 vs. day 1 ([italic]P[/italic][lt]0.001) as predicted from linear pharmacokinetics. Mean CL[sub]R[/sub] estimates for RWJ-333369 were [lt]5% of the mean oral clearance, suggesting the primary mechanism for elimination of RWJ-333369 is through metabolism prior to renal excretion. Eight subjects dropped out of the study, 3 while receiving placebo and 5 while receiving RWJ-333369 (of whom only 3 had adverse events considered possibly or probably related to study drug at 500 mg and 750 mg bid; 2 dropped out due to other reasons). RWJ-333369 exhibits linear PK after single (100-1500mg) and repeated (100-750 mg q12h) doses. It is rapidly absorbed and has a mean elimination half life of 11.5-13.9 h, allowing q12h dosing. Following q12h administration, RWJ-333369 accumulates two-fold; the primary mechanism of elimination is through metabolism. (Supported by Johnson [amp] Johnson PRDUS, LLC and SK Bio-Pharmaceuticals.)