Acute and long‐term effects of brivaracetam and brivaracetam–diazepam combinations in an experimental model of status epilepticus

OBJECTIVE: To evaluate acute and long‐term effects of intravenous brivaracetam (BRV) and BRV + diazepam (DZP) combination treatment in a rat model of self‐sustaining status epilepticus (SSSE). METHODS: Rats were treated with BRV (10 mg/kg) 10 min after initiation of perforant path stimulation (PPS) as early treatment; or BRV (10–300 mg/kg), DZP (1 mg/kg), or BRV (0.3–10 mg/kg) + DZP (1 mg/kg) 10 min after the end of PPS (established SSSE). Seizure activity was recorded electrographically for 24 h posttreatment (acute effects), and for 1 week at 6–8 weeks or 12 months' posttreatment (long‐term effects). All treatments were compared with control rats using one‐way analysis of variance (ANOVA) and Bonferroni's test, or Kruskal‐–Wallis and Dunn's multiple comparison tests, when appropriate. RESULTS: Treatment of established SSSE with BRV (10–300 mg/kg) resulted in dose‐dependent reduction in SSSE duration and cumulative seizure time, achieving statistical significance at doses ≥100 mg/kg. Lower doses of BRV (0.3–10 mg/kg) + low‐dose DZP (1 mg/kg) significantly reduced SSSE duration and number of seizures. All control rats developed spontaneous recurrent seizures (SRS) 6–8 weeks after SSSE, whereas seizure freedom was noted in 2/10, 5/10, and 6/10 rats treated with BRV 200 mg/kg, 300 mg/kg, and BRV 10 mg/kg + DZP, respectively. BRV (10–300 mg/kg) showed a dose‐dependent trend toward reduction of SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at 300 mg/kg. Combination of BRV (10 mg/kg) + DZP significantly reduced SRS frequency, cumulative seizure time, and spike frequency. In the 12‐month follow‐up study, BRV (0.3–10 mg/kg) + low‐dose DZP markedly reduced SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at some doses. Early treatment of SSSE with BRV 10 mg/kg significantly reduced long‐term SRS frequency. SIGNIFICANCE: These findings support clinical evaluation of BRV for treatment of status epilepticus or acute repetitive seizures.