Abstracts

Rationale: The overall 70% efficacy rate for treatment of SE by AEDs (Yasiry & Shorvon, Seizure 2014) is still not considered optimal, prompting calls for better AED treatments for SE. One of the key issues in treatment of SE is time to AED effect; to reduce, as much as possible, the negative effects of prolonged epileptic activity; and anoxia on brain function. Standardized comparative trials in SE are very difficult to perform due to variability in occurrence, severity of status, time to reach the hospital and medications already given by family members, general practitioners and first aid staff. The "Photosensitivity Model" (Kasteleijn- Nolst Trenit頥t al., 2015), with its adaptive design possibilities, can accomplish this pharmacodynamic comparison (rapidity of the CNS effects) in an elegant, standardized and controlled way. Methods: We took as an example comparison of iv-LEV and iv-BRV, based on our knowledge of both drugs on PD after single doses in the "Photosensitivity Model" (Kasteleijn- Nolst Trenite et al., 1996, 2007). PET imaging data in rhesus monkeys (Mercier et al., 2014) showed a more rapid, 1-min brain entry for BRV versus that of a 28 min entry for LEV. Equivalent to human doses were 1500 mg LEV and 100 mg BRV in this PET study. Timing of the PPR measurements were adapted to the fast entry of the drugs and our intent to find the 'time to effect' precisely. Analysis of differences in time to effect will be done with a two group t-test (Crossover ANOVA) with a 0.050 two-sided significance level. Results: We adapted the "Photosensitivity Model" into a prospective, randomized, crossover, controlled intravenous study using the evoked photoparoxysmal EEG response (PPR) as a pharmacodynamic efficacy endpoint to compare two different AEDs. 1. Conduct an intra-patient comparison of three pharmacodynamic metrics (time to effect, time to peak effect, and magnitude of effect), in adult photosensitive epilepsy patients from time zero up to the first two (2.0) hours after: a. a 15-minute zero-order infusion of either LEV 1500 mg dose versus an equipotent dose of BRV 100 mg, given on two separate occasions in random, crossover, double-blind fashion (n = 8 patients, as [Study Part 1]); b. a single intravenous five (5)-minute infusion dose of either LEV 1500 mg versus an equipotent dose of BRV 100 mg, given on two separate occasions in random, crossover, double-blind fashion (n = 8 patients; [Study Part 2, Option I]); OR c. a single intravenous five (5)-minute infusion dose of either LEV 500 mg versus an approximately equi-potent dose of BRV 25 mg, given on two separate occasions in random, crossover, double-blind fashion (n = 8 patients; [Study Part 2, Option II]). Conclusions: The "Photosensitivity Model", with its adaptive possibilities, allows us to examine differences in time to CNS entry and effect on epileptiform discharges with optimal dose and rapid infusion time of AEDs. Funding: None