Abstracts

Rationale: A diazepam nasal spray (D-NS) formulation is under development for treating cluster seizures. This study was designed to determine the feasibility of administration and pharmacokinetics (PK) of D-NS by seizure type and status following a single dose of administration in adults with epilepsy. Additional goals were safety and tolerability.Methods: A multi-center, open-label, PK study was conducted in adults admitted to the epilepsy monitoring unit (EMU) for evaluation and management of epilepsy. Prior antiepileptic drugs were discontinued or reduced in most patients during their stay at the EMU. Following standard EMU treatment protocols, when an acute benzodiazepine was indicated, eligible patients received a single dose of D-NS approximating 0.2 mg/kg bodyweight. Patients were observed and plasma diazepam concentrations were measured serially up to 12 h post-dose. PK parameters for Cmax, Tmax, and AUC0-12 were estimated using noncompartmental analyses. Dosing time relative to seizure, type of seizure, time to first post-dose seizure and use of rescue medication (intravenous lorazepam) for post-dose seizure were recorded. Safety parameters and tolerability were assessed.Results: Thirty-one patients were dosed; mean age was 35 years (range 18-65). Thirty patients had post-dose PK data. Ten patients were dosed during the ictal state of a tonic-clonic (TC) seizure, 7 were dosed 5 min following the last clonic jerk, and 13 were dosed in the post-ictal period ( 5 min after a TC seizure, n=4) or for other seizure types (n=9). Mean plasma diazepam concentrations for those dosed during TC ictal state relative to all others were similar. Dose-normalized Cmax and AUC0-12 were also similar in the two groups; 194 versus 216 ng/mL and 1258 versus 1212 h.ng/mL, respectively. The similarities in PK profiles between the two groups indicated the feasibility of D-NS administration during a TC seizure and that dosing was not affected by seizure status or type. Of those dosed, 20 (65%) were seizure-free during the 12-h observation period whereas the remaining 11 (35%) had post-dose seizures with an average of 4.8 h to first post-dose seizure. Three (10%) received additional rescue medication during the 12-hr observation period with a mean time of 5.2 h to medication administration. Treatment was well-tolerated with 74% of adverse events graded as mild and 25% as moderate. The most common adverse events were related to the route of administration, including dysgeusia (26%), nasal discomfort (23%), increased lacrimation (16%), rhinorrhoea (16%), oropharyngeal pain (13%), paranasal sinus hypersecretion (13%), nasal congestion (10%), parosmia (10%), and throat irritation (7%).Conclusions: Results confirmed that D-NS can be administered to patients experiencing an epileptic seizure, and that administration was not affected by seizure type or status at the time of dosing. D-NS was generally well tolerated with most adverse events related to route of administration. Funding: Neuronex, Inc, and Acorda Therapeutics, Inc.