Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjects.
OBJECTIVE
To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations.


METHODS
An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5-8; subsequently, 500 mg on days 9-12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry.


RESULTS
Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80-125% limits, which are considered not to be of clinical significance. With dose-body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80-125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1-41.4 ml/h/kg and 11.5-12.8 h.


CONCLUSIONS
Carisbamate plasma exposure (AUC) and C(max) in Japanese subjects is approximately 20-25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality.
Zannikos
Peter
P
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA.
Novak
Gerald
G
Yao
Caiping
C
Verhaeghe
Tom
T
Franc
Monique A
MA
Solanki
Bhavna
B
Bialer
Meir
M
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000927:Anticonvulsants / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D002138:Calibration; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D012016:Reference Values; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors; D044465:White People; D055815:Young Adult
D000927:Anticonvulsants; D002219:Carbamates; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol