Abstracts

Rationale: There is an unmet medical need in the out-of-hospital management of seizure emergencies because many older children and adults often refuse treatment with diazepam rectal gel due to social objections. Consequently, many patients fail to realize the benefit of a therapy that can improve outcomes and decrease healthcare costs. Our preliminary studies [1, 2] have demonstrated that intranasal diazepam administration is feasible, resulting in a Cmax and Tmax that are comparable to rectal diazepam. However, the tolerability of our initial formulation was poor, which rendered it unsuitable for further development. In the present study, we compared the tolerability and pharmacokinetics of two new investigational nasal formulations with diazepam rectal gel. Methods: Two intranasal diazepam formulations (SK Pharmaceuticals-Seoul, Korea), given as three treatments (Nas-A 10 mg, Nas-B 10 mg and 13.4 mg), were compared with the diazepam rectal gel (10 mg). Twelve healthy volunteers were enrolled into this active-control, double-blinded, four-period, crossover study which was sponsored by Valeant Pharmaceutical, CA. A single dose of each diazepam formulation was administered followed by at least a 14 day washout period. Blood for diazepam analysis were collected pre-dose and at regular intervals up to 240 hours post-dose. Plasma samples were assayed by high performance liquid chromatography and pharmacokinetic analysis was performed on the diazepam concentration-time data. Visual analog scales were used to assess tolerability (1-tolerable; 10-extremely intolerable) and sedation 1-5 (1- alert; 5 -sleeping) at predefined time points. Results: Results of the pharmacokinetic analysis are presented in the table below. Immediately following administration, subjects reported tolerability scores of 2.6, 1.6 and 1.4 for the three intranasal treatments, and sedation scores of 1.0, 1.4 and 1.1 were reported 2 hours after administration. In comparison the tolerability and sedation scores for rectal diazepam were 0.3 and 0.8 respectively. All subjects reported swallowing a fraction of the dose and the presence of bad aftertaste for all intranasal treatments. All subjects expressed a preference for the nasal versus rectal route for treatment of seizure emergencies. Conclusions: Both investigational intranasal diazepam formulations were well tolerated and exhibited relatively rapid, but variable, absorption. The relative bioavailability was good and consistent with previous studies as was the slow decline in plasma diazepam concentrations. These results are comparable to results from the diazepam rectal gel arm of the study, suggesting that intranasal diazepam offers a viable alternative to rectal administration. Reducing the variability in the pharmacokinetics and improving the taste of the formulation would be helpful.