Abstracts

Rationale: Seizure emergencies (SE) are defined as either seizure clusters or episodes lasting at least 5 minutes. For the last 2 decades, rectal diazepam has been the mainstay of out-of-hospital SE management, but many older children and adults object to this mode of therapy. Development of intranasal (IN) diazepam (DZP) and midazolam (MDZ) formulations is underway. These products have the potential to offer safe, effective, and more socially acceptable treatment options. However, first generation IN therapies have limitations such as suboptimal rates of absorption, variable bioavailability, and reliance on organic solvents. Our group is developing a novel intranasal drug delivery system involving the synthesis of water-soluble benzodiazepine prodrugs that are admixed with converting enzymes at the time of administration. As a first iteration, avizafone (AVF), a water-soluble DZP prodrug, was synthesized and combined with Aspergillus oryzae protease (AOP), which rapidly converts AVF to DZP resulting in supersaturated concentrations of the active drug in the nasal mucosa. The aim of the present pilot study was to evaluate the pharmacokinetics (PK) of our system in rats. Methods: Six rats received an intranasal (IN) dose of an admixture of AVF (1.6mg/kg, which is equivalent to 1.1mg/kg DZP) and AOP (3.6 Units) prepared just prior to administration. Three rats were sacrificed at 5 min post-dose and brain and blood samples were collected. Blood samples were also collected from the other animals at specified times ranging from 15 to 90 min post-dose. Plasma and brain DZP concentrations were measured by a validated HPLC-UV method. PK parameters were determined using non-compartmental analysis. Results: The mean ( SD) maximum DZP concentration, 450 ng/mL ( 53.7 ng/mL), was attained at 5 min post-dose. Brain and plasma DZP concentrations at 5 min post-dose were similar with a mean brain to plasma ratio of 0.88 0.08. Distribution volume, elimination half-life, and clearance were 5 L/kg, 40 minutes, and 5.4 L/hr/kg, respectively. Conclusions: This pilot study demonstrates the feasibility of a novel delivery system as a rescue therapy. Following IN dosing of the water-soluble prodrug/enzyme combination, DZP concentrations were similar to those reported after a 1mg/kg intravenous DZP dose in rats (Paramjeet et al., Int J of Pharmaceutics, 2008). This indicates that a high percentage of the prodrug is converted to DZP and absorbed through the nasal mucosa. This prodrug/enzyme system obviates the need for organic solvents, hence reducing the risk of adverse effects. Further, the supersaturated DZP concentrations produced at the site of administration result in very rapid absorption, offering the potential of a faster onset of action. The ease of use and social acceptability of this alternative rescue therapy should result in a greater acceptability by patients leading to fewer emergency room visits and an improved quality of life. In future studies, we plan to characterize the safety and toxicity of DZP and MDZ prodrugs in rodents and, subsequently, their PK and efficacy in dogs with seizures. Funding: Clinical and Translational Science Institute, Academic Health Center, and College of Pharmacy, University of Minnesota; American Epilepsy Society, Epilepsy Foundation