Abstracts

Rationale: JZP-4 (3-(2,3,5-trichloro-phenyl)-pyrazine-2,6-diamine) is a novel use-dependent and voltage-dependent inhibitor of sodium and calcium channels which is currently being evaluated as an anticonvulsant and mood stabilizer. The antiepileptic drug lamotrigine (LTG) is known to reduce cortical excitability as measured by transcranial magnetic stimulation (TMS). Although JZP-4 is structurally related to lamotrigine (LTG), it is more potent and active at both sodium and calcium channels, has a different metabolic pathway and a shorter half life. Previous TMS studies have shown that a single oral dose of LTG increases motor cortical inhibition by increasing resting motor threshold (rMT) three hours post-dosing. rMT is regulated by voltage-gated ion channels. We used TMS to determine the effective dose ranges at which single oral doses of JZP-4 inhibited human motor cortical activity. Lamotrigine was used as a positive control and active comparator in this study. Methods: We performed a double-blind, ascending dose, placebo-controlled crossover study involving 6 visits with a minimum 7-day washout period between each visit. Eleven healthy male subjects received one of the following doses each week in an ascending order: JZP-4 (at either 50, 100, 150, or 200 mg), LTG (325 mg) and placebo. rMT and serum levels were measured at baseline (pre-dose) and at 1, 3, 5 and 8 hours post-dose. Results: LTG and all doses of JZP-4 increased rMT when compared to placebo. Statistically significant peak rMTs (percentage change from baseline ± SD) occurred at 3 hours (5.7 +/- 4.52) and 5 hours (3.9 +/- 5.09) post-dose for LTG, 325 mg. Statistically significant peak rMTs for JZP-4 occurred as follow: 50 mg, 3 hours (3.4 +/- 7.2) and 5 hours (2.1 +/- 6.4); 150 mg, 8 hours (3.3 +/- 5.7); 200 mg, 8 hours (2.2 +/- 8.4) post dose. The most commonly reported adverse events were dizziness, somnolence and headache. Conclusions: Single oral dose of JZP-4 at doses ranging from 50 to 200 mg increase rMT when compared to placebo. All doses resulted in an increase of rMT that was within the range of that produced by LTG. The effect of LTG on rMT was consistent with previously published studies. TMS measures of cortical excitability are useful in measuring the effects of some classes of anticonvulsant drugs and help determine an effective initial dose range to be used in larger clinical trials. Source of funding: Jazz Pharmaceuticals.