Pharmacokinetics and safety of brivaracetam in neonates with repeated electroencephalographic seizures: A multicenter, open-label, single-arm study.

OBJECTIVE: To evaluate the pharmacokinetics (PK), safety and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs).

METHODS: Phase 2/3, multicenter, open-label, single-arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 seconds) confirmed by video-electroencephalography, and inadequate seizure control with ≥1 ASMs. A screening period (up to 36 hours) was followed by a 48-hour evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment-emergent adverse events (TEAEs).

RESULTS: Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All 6 patients completed the evaluation period; 2 entered and completed the extension period. Overall (evaluation and extension periods), 3 patients received 1 dose of 0.5 mg/kg BRV and 3 received >1 dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n=6). At 0.5-1, 2-4, and 8-12 hours following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n=5]), 0.50 mg/L (28.20% [n=6]) and 0.34 mg/L (13.20% [n=5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced 4 TEAEs, none of which were considered related to BRV.

SIGNIFICANCE: BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg twice daily. BRV was well-tolerated, with no drug-related TEAEs reported.