TY - JOUR
T1 - Pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple dosing to humans
AU - Yao, Caiping
AU - Doose, Dennis R.
AU - Novak, Gerald
AU - Bialer, Meir
PY - 2006/11
Y1 - 2006/11
N2 - 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 (t1/2) 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. Cmax 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.
AB - 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 (t1/2) 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. Cmax 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.
KW - Food effect
KW - Healthy subjects
KW - New antiepileptic drug
KW - Pharmacokinetics
KW - RWJ-333369
UR - http://www.scopus.com/inward/record.url?scp=33750900787&partnerID=8YFLogxK
U2 - 10.1111/j.1528-1167.2006.00814.x
DO - 10.1111/j.1528-1167.2006.00814.x
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C2 - 17116021
AN - SCOPUS:33750900787
SN - 0013-9580
VL - 47
SP - 1822
EP - 1829
JO - Epilepsia
JF - Epilepsia
IS - 11
ER -