Abstracts

Rationale: Ganaxolone (GNX) is the 3߭methylated analog of the naturally occurring neurosteroid allopregnanolone. GNX acts as a positive allosteric modulator of both the synaptic (comprised of a and ? subunits) and extrasynaptic (comprised of a and d subunits) GABAA receptor. In contrast, benzodiazepines only modulate the synaptic GABAA receptor. The benzodiazepine sensitive synaptic GABAA receptor rapidly desensitizes during seizures and with repeated benzodiazepine administration. In contrast, the extrasynaptic GABAA receptor remains responsive to GNX during seizure events and does not desensitize with repeat GNX treatment. In preclinical animal models, GNX effectively blocks seizures in a broad range of experimental epilepsies and is in clinical development for the treatment of various epileptic conditions. In recent preclinical studies we demonstrated that IV-administered GNX blocked seizures in a clinically translatable model of benzodiazepine resistant status epilepticus (SE). The current studies were conducted to expand those findings by assessing the effects of the combination of IV-administered GNX and diazepam on experimental SE. Methods: SE was induced by the administration of lithium chloride and pilocarpine to adult male Sprague-Dawley rats. Seizure response was measured by electroencephalographic (EEG) recordings through pre-implanted cortical electrodes. GNX and/or diazepam were administered sequentially 15 minutes after SE onset. In a parallel group of rats, blood was collected and GNX and diazepam plasma levels assessed to evaluate pharmacokinetic interactions. Results: Pilocarpine-induced seizures were sustained for approximately 6 hrs and were resistant to diazepam infusion up to a dose-level of 10 mg/kg. In a previous study, GNX at dose-levels of less than 12 mg/kg were inactive in the SE model whereas higher dose-levels were completely protective. In the current studies, diazepam at a subtherapeutic dose-level of 5 mg/kg in combination with GNX administered at subtherapeutic dose-levels of 3 or 6 mg/kg blocked SE for ~1 and over 3 h repectively. The plasma levels and pharmacokinetic parameters of both GNX and diazepam were identical whether administered alone or in combination. Conclusions: GNX and diazepam administered at subtherapeutic dose-levels produced a synergistic reduction in the SE-response as measured by EEG seizure events. The identical pharmacokinetics of both drugs when administered alone or in combination indicates that neither drug affected the pharmacokinetic disposition of the other. These data suggest that the synergistic enhancement of anti-epileptic activity occurred at the mechanistic level and implicates a combinatorial effect on the GABAA receptor. Further, these data have clinical implications in the treatment of SE when GNX is to be administered to patients who are or have been treated with benzodiazepines. Funding: These studies were funded by Marinus Pharmaceuticals, Inc.