Diazepam rectal gel (Diastat(®)) is the only FDA-approved product indicated for acute repetitive
seizures. Despite its proven efficacy, most 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 of two novel intranasal (IN)
diazepam (DZP) formulations versus intravenous (IV) administration in healthy volunteers. Twenty-four healthy volunteers were randomized into an open-label, three-way crossover study. 10mg doses of two investigational intranasal DZP formulations (
solution,
suspension) and a 5mg IV dose of commercially available 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 h post-dose. DZP concentration-time data were analyzed using a non-compartmental pharmacokinetics approach. Exposure following administration of DZP IN
solution (absolute bioavailability - 97%) was greater than the IN
suspension (absolute bioavailability - 67%). Mean Cmaxvalues for the
suspension and
solution formulations were 221 ng/mL and 272 ng/mL, respectively. Median time to maximum concentration (Tmax) was 1h and 1.5h for
suspension and
solution formulation, respectively. Both investigational intranasal formulations were well tolerated. The results of this pilot study indicate that development of an intranasal
diazepam formulation with high bioavailability, reasonable variability, and good tolerability is feasible.