Abstracts

Rationale: Diazepam rectal gel (Diastat ) is the only FDA-approved diazepam product indicated for acute repetitive seizures. Despite the proven efficacy of rectal diazepam, older children and adults object to this route of administration. As a result, many patients do not realize the benefit of a therapy that can improve outcomes and decrease healthcare costs. Intranasal administration of benzodiazepines offers a potential alternative. The primary objective of this study was to compare the bioavailability and pharmacokinetics (PK) of two novel intranasal (IN) diazepam (DZP) formulations versus intravenous (IV) administration in healthy volunteers. Methods: Following provision of informed consent, 24 healthy volunteers were randomized into an open-label, three-way crossover study. Ten mg doses of two investigational intranasal DZP formulations (solution, suspension) and a 5 mg IV dose of DZP Injectable, USP were given. A two-week washout period separated treatments. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 240 hours post-dose. DZP concentration-time data were analyzed using a non-compartmental pharmacokinetics approach (Phoenix WinNonLin vr 6.2; Pharsight Corporation, Mountain View, CA, USA). Repeated measures ANOVA followed by post hoc Dunnett test was used to test for statistical differences in AUC and T_1/2 among the IN and IV formulations . A paired t test was used to test for a statistical difference in Cmax and Bioavailability and the Wilcoxon matched-pairs signed-ranks test was used to test the statistical difference in Tmax between the two IN formulations.Results: A summary of the pharmacokinetic parameters is presented in the Table. Bioavailability of the IN solution approached 100% and was significantly (p < 0.05) greater than the IN suspension, as was Cmax. Median time to maximum concentration (Tmax) was 1hr and 1.5hr for suspension and solution formulation, respectively. The mean T_1/2 was similar for all three formulations. Both investigational intranasal formulations were well tolerated.Conclusions: The absolute bioavailability of the IN Solution was higher than that reported in prior intranasal diazepam and midazolam studies, while variability in exposure (AUC) for both the suspension and the solution was similar to the IV dose. The results of this pilot study indicate that development of an intranasal diazepam formulation with high bioavailability, relatively low variability, and good tolerability is feasible. Acknowledgements: This study was funded by a grant from Neurelis, Inc, which also provided the test formulation.