Abstracts

Rationale: FDA-approved diazepam rectal gel has been successfully used in the out-of-hospital management of seizure emergencies. Older children and adults, however, often refuse this treatment due to objections to the route of administration. As a result many patients do not realize the benefit from a therapy that can improve outcomes and decrease healthcare costs. We hypothesized that the availability of a fast acting intranasal treatment that is easily administered by the patient or a caregiver would improve the management of seizure emergencies. The purpose of this study was to investigate the bioavailability, dose proportionality and tolerability of a super-saturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol-water cosolvent system. Methods: Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare the pharmacokinetics and tolerability of two intranasal DZP doses (5 and 10 mg) of the investigational formulation with a 5 mg dose of a commercially available parenteral DZP solution (DZP injectable, 5 mg/ml, USP) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48 hours post-dose. Samples were assayed by high performance liquid chromatography and pharmacokinetic analysis was performed on the DZP concentration-time data. Visual analog scales were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1- no pain; 4 -extreme pain) at predefined time points. Results: Median tmax was 20-30 minutes and the mean Cmax for the 5 and 10 mg does were 134.3 ± 62 ng/mL and 247.6 ± 61 ng/mL. The estimated bioavailability of the intranasal formulation was 75%. AUC0-t increased approximately proportionally with dose. The mean t1/2 (49.1-57.0 h) was independent of dose. Immediately following intranasal administration, subjects reported tolerability scores of 6.75 and 6.0, and identical pain scores, 3.2, for the 5 and 10 mg intranasal doses, respectively. Both the tolerability and pain scores returned to baseline values within 15 minutes. However, 2 subjects reported scores of 8 or more for more than 15 minutes. Conclusions: An investigational intranasal DZP formulation exhibited relatively rapid absorption and good bioavailability with a slow decline in plasma DZP concentrations. These results suggest that intranasal DZP offers a viable alternative to rectal administration. However, improved tolerability is needed in order to permit clinical use.