Abstracts

Because of the metabolic induction capability of carbamazepine (CBZ), there is a potential for interaction when CBZ is used adjunctively with other drugs. This study investigated pharmacokinetic (PK) interactions, safety and tolerability between 2 dosing regimens of RWJ-333369, a novel neuromodulator currently under development for epilepsy, and CBZ. In an 8-wk, open-label, sequential-design study, 24 healthy adults [ge]18 and [le]60 yrs 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 a combination of CBZ (300 mg q12h) and RWJ-333369 (5 days 250 mg q12h; 5 days 500 mg q12h) for 10 days. RWJ-333369 plasma concentrations were at steady state on day 6 for 250 mg q12h dosing and on day 10 for 500 mg q12h dosing. RWJ-333369 C[sub]max[/sub] and AUC[sub]0-12 [/sub]increased in proportion to dose; T[sub]max[/sub] was dose-independent. CBZ C[sub]max[/sub] and AUC[sub]0-12 [/sub]were similar with and without RWJ-333369. The 90% confidence intervals for the C[sub]max[/sub] and AUC[sub]0-12[/sub] of CBZ were 94-104% and 95-104%, respectively, well within the equivalence range 80-125%. When RWJ-333369 was coadministered with CBZ, mean C[sub]max [/sub]and AUC[sub]0-12 [/sub]were reduced by [sim]30% and 40%, respectively. Oral clearance was increased by 60%, and t[sub]1/2 [/sub]was shortened by about 3 h (Table). Four subjects discontinued the CBZ treatment, and 1 subject the concomitant treatment due to adverse events. There was no effect of multiple-dose RWJ-333369 on CBZ PK. CBZ induced RWJ-333369 clearance, resulting in decreased C[sub]max[/sub], AUC[sub]0-12[/sub], and t[sub]1/2[/sub] of RWJ-333369. Concomitant administration of RWJ-333369 with CBZ was generally safe and well tolerated in this study.[table1] (Supported by Johnson [amp] Johnson PRDUS, LLC.)