Abstracts

Rationale: There are a limited number of marketed intravenous antiepileptic drugs, of which only a few have been well studied for status epilepticus (SE). All were first developed for chronic therapy of epilepsy. Epilepsy and SE occur naturally in dogs with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. These circumstances make it possible to evaluate novel AEDs developed only for SE in clinical canine cases.Methods: Informed consent was obtained from the owners of dogs with SE. Dogs who failed initial benzodiazepine (BZD) treatment were randomized to an IV infusion of 15mg/kg phenytoin equivalent (PE) (n=11) of the human formulation of fosphenytoin (FOS) or to saline placebo (PBO) (n=9). Blood pressure, EKG, and vital signs were monitored. If seizures continued, additional IV BZD or IV phenobarbital was administered per the standard of care for veterinary patients. Dogs were observed for 12 hours and total and unbound plasma phenytoin (PHT) concentrations were measured. Results: In the FOS group, total plasma PHT concentrations at 30 mins ranged from 6.92 to 13.81 mcg/ml. Interim analysis of 20 enrolled patients showed that that 72% of those in the FOS group had no further seizures vs. 0% in the PBO group (p=0.0031). The mean number of seizures within 12 hours post study intervention was 0.23 (95% CI 0.074-0.72) in the FOS group vs. 1.86 (95% CI 1.08-3.20) in the PBO group (p=0.0011). There were no statistically significant differences in adverse events between the groups, except for some transient minor vomiting in the FOS group. It is anticipated that a total of 30 or more cases will enrolled by the fall of 2013, and the correlation between PHT levels and response will also be analyzed.Conclusions: This proof of concept study provides the first evidence that FOS is well tolerated and effective in canine SE. Further, naturally occurring canine SE can be utilized as a translational platform for studies of novel compounds that bridge laboratory studies in rodent models with human SE trials.