Abstracts

RWJ-333369 is a novel neuromodulator under development for the treatment of epilepsy. As valproate (VPA) and lamotrigine (LTG) are commonly used in patients with epilepsy, and all 3 drugs involve uridine diphosphate glucuronyl transferase metabolism, potential pharmacokinetic (PK) interactions, as well as safety and tolerability were evaluated at clinically relevant doses. Two 6-9 wk, open-label, sequential design studies were conducted. In study 1, 24 healthy adults [ge]18 and [le]60 yrs received RWJ-333369 alone (10 doses 250 mg q12h; 11 doses 500 mg q12h). After a 4-day washout, they received VPA alone (14 doses 300 mg q12h; 14 doses 500 mg q12h), then RWJ-333369 (10 doses 250 mg q12h; 11 doses 500 mg q12h) with VPA (500 mg q12h) for 21 combined doses. In study 2, 24 healthy subjects [ge]18 and [le]60 yrs received RWJ-333369 (10 doses 250 mg q12h; 10 doses 500 mg q12h) alone, LTG (28 doses 25 mg q12h; 29 doses 50 mg q12h) alone, and RWJ-333369 (6 doses 250 mg q12h; 28 doses 500 mg q12h) with LTG (50 mg q12h) for 34 combined doses. In study 1, coadministration of multiple-dose VPA with RWJ-333369 had minimal effect on RWJ-333369 C[sub]max[/sub] and AUC[sub]0-12[/sub]. The 90% confidence intervals (CIs) for C[sub]max[/sub] and AUC[sub]0-12[/sub] of RWJ-333369 were 101-110% and 105-110%, respectively; well within the equivalence range 80-125%. Concomitant administration with RWJ-333369 500 mg q12h slightly reduced VPA C[sub]max[/sub] and AUC[sub]0-12 [/sub]by [sim]15% and increased oral clearance by [sim]20%. However, the 90% CIs for C[sub]max[/sub] and AUC[sub]0-12[/sub] of VPA were within the equivalence range 80-125% (82-89% for C[sub]max[/sub] and 81-88% for AUC[sub]0-12[/sub]). These effects are not clinically significant.
In study 2, coadministration of multiple-dose LTG with RWJ-333369 had minimal effect on C[sub]max [/sub]and AUC[sub]0-12 [/sub]of RWJ-333369. The 90% CIs for C[sub]max[/sub] and AUC[sub]0-12[/sub] of RWJ-333369 were 93-102% and 93-98%, respectively, well within the equivalence range 80-125%. Coadministration of RWJ-333369 500 mg q12h reduced LTG C[sub]max [/sub]and AUC[sub]0-12 [/sub]by [sim]20%; the 90% CIs were slightly below the 80-125% equivalence range (79-86% for C[sub]max[/sub] and 75-81% for AUC[sub]0-12[/sub]). This modest change achieved statistical significance but is not considered clinically significant.
There were no serious adverse events or adverse events that led to discontinuation of treatments in either study. There were no clinically significant interactions between RWJ-333369 and VPA or LTG. Concomitant administration of RWJ-333369 with VPA or LTG had minimal effects on PK parameters of RWJ-333369. Concomitant RWJ-333369 reduced VPA and LTG exposure by [sim]20%, which is not considered to be of clinical significance. Concomitant administration of RWJ-333369 with VPA or LTG was generally safe and well tolerated in these studies. (Supported by Johnson [amp] Johnson PRDUS, LLC.)