Pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple dosing to humans.
OBJECTIVE
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.


METHODS
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.
Yao
Caiping
C
Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Raritan and Titusville, NJ, USA.
Doose
Dennis R
DR
Novak
Gerald
G
Bialer
Meir
M
D000284:Administration, Oral; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D002219:Carbamates / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015507:Drugs, Investigational; D018565:Food-Drug Interactions; D006801:Humans; D018377:Neurotransmitter Agents / Q000493:pharmacokinetics*; D010919:Placebos
D000927:Anticonvulsants; D002219:Carbamates; D015507:Drugs, Investigational; D018377:Neurotransmitter Agents; D010919:Placebos