Pharmacokinetic interaction study between the new antiepileptic and CNS drug RWJ-333369 and carbamazepine in healthy adults.
OBJECTIVE
To characterize the possible pharmacokinetic interaction between the new antiepileptic and CNS drug RWJ-333369 and carbamazepine (CBZ) following multiple dosing in healthy subjects.


METHODS
In an 8-week, open-label, sequential design study, 24 healthy adults received multiple-dose RWJ-333369 alone (5 days 250 mg q12h; 5 days 500 mg q12h), then after a 4-day washout, multiple-dose CBZ alone (3 days 100 mg q12h; 3 days 200 mg q12h; 22 days 300 mg q12h), and then combination of CBZ (300 mg q12h), and RWJ-333369 (5 days 250 mg q12h; 5 days 500 mg q12h).


RESULTS
At steady-state following multiple dosing, RWJ-333369 peak plasma concentration (C(max)) and area under the concentration-time-curve within the dosing interval (AUCss) increased in proportion to dose. The C(max) and AUCss of CBZ were similar when given alone or concomitantly with RWJ-333369. The 90% confidence intervals for the ratio of CBZ C(max) and AUCss with/without RWJ-333369 were: 94-104% and 95-104%, respectively (well within the equivalence range of 80-125%). When RWJ-333369 was administered with CBZ, its mean (SD) oral clearance increased from 3.2 L/h to 4.9 L/h and consequently its mean half-life was shortened from 10.4 (1.9) h to 7.4 (1.2) h, and mean AUCss and C(max) were reduced by 37% and 30%, respectively.


CONCLUSIONS
There was no effect of multiple-dose RWJ-333369 on CBZ pharmacokinetics. CBZ induced RWJ-333369 clearance, resulting in shortened half-life and decreased exposure (AUCss) and C(max). Concomitant administration of RWJ-333369 with CBZ was generally safe and tolerated.
Chien
Suchean
S
Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Raritan and Titusville, New Jersey, USA.
Bialer
Meir
M
Solanki
Bhavna
B
Verhaeghe
Tom
T
Doose
Dennis R
DR
Novak
Gerald
G
Yao
Caiping
C
D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015195:Drug Design; D004347:Drug Interactions; D015507:Drugs, Investigational; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000097:blood / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D002219:Carbamates; D015507:Drugs, Investigational; D018377:Neurotransmitter Agents; D002220:Carbamazepine