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. JZP-4 was shown to be active in several animal models of epilepsy (Foreman MM et al. 2008). In this study JZP-4 was evaluated in patients with photo paroxysmal EEG responses (PPR) to intermittent photic stimulation (IPS), a method that has been previously shown to be helpful in assessing the antiepileptic properties of a molecule. This study represents the first evaluation of JZP-4 in epilepsy patients. Methods: We performed a single-blind, placebo-controlled, comparative, within subject ascending dose, exploratory study in four photosensitive epilepsy patients on one or two antiepileptic drugs. Three males and one female received single doses of JZP-4 ranging from 25 to 200 mg, a single dose of 1000 mg valproic acid (VPA) or 1000 mg levetiracetam (LEV), and placebo. PPR ranges were measured in 3 different eyes conditions (eye closure, eyes closed, eyes open) every hour up to 8 hours post-dose during three days of testing per JZP-4 dose. Serum levels were measured 1, 3, 5 and 8 hours post-dose. Results: VPA, LEV and doses of JZP-4 ranging from 50 mg to 200 mg decreased paroxysmal responses to IPS in all subjects tested. The optimal antiepileptic effect of JZP-4 was seen approximately 5 hours post-dose where complete suppression of photosensitivity was observed. The most commonly reported adverse events were somnolence and dizziness. Conclusions: This exploratory study is the first report that JZP-4 possesses antiepileptic properties in epilepsy patients. A single oral dose of JZP-4 at doses ranging from 50 to 200 mg decreased paroxysmal responses to IPS when compared to placebo. The effect of JZP-4 was comparable to that of VPA, 1000 mg. LEV was generally more active than VPA or JZP-4 in this model. Source of funding: Jazz Pharmaceuticals.