Pharmacokinetics, safety, and tolerability of intravenous brivaracetam in pediatric patients with epilepsy: An open-label trial

Abstract

Objective: To evaluate the pharmacokinetics, safety, and tolerability of brivaracetam (BRV) as 15-min intravenous (IV) infusion and bolus (≤2-min injection).

Methods: EP0065 (ClinicalTrials.gov: NCT03405714) was a Phase 2, multicenter, open-label trial in patients ≥1 month to <16 years of age with epilepsy. Patients received up to 5 mg/kg/day BRV (not exceeding 200 mg/day). Enrollment was sequential by descending age, depending on safety review. Outcomes included BRV plasma concentrations before and after IV administration, treatment-emergent adverse events (TEAEs), and discontinuations due to TEAEs.

Results: Fifty patients were enrolled, received BRV, and completed the trial. Twenty-six patients (52.0%) received 15-min infusions and 24 (48.0%) received bolus injections. Most patients (80.0%) received one IV dose. In the 15-min infusion group, geometric mean (GeoMean) BRV concentrations 15 (±2) min (n = 21) and 3 h (±15 min) (n = 21) post dose were 1903.0 ng/mL (geometric coefficient of variation [GeoCV]: 60.7%) and 1130.3 ng/mL (58.8%), respectively. In the bolus group, GeoMean BRV concentrations 15 (±2) min (n = 19) and 3 h (±15 min) (n = 21) post dose were 1704.8 ng/mL (GeoCV: 74.5%) and 1383.9 ng/mL (85.0%), respectively. Overall, 14 patients (28.0%) had TEAEs (15-min infusion: 8 [30.8%]; bolus: 6 [25.0%]), most commonly (≥5% of patients) somnolence (3 [6.0%]). Ten patients (20.0%) had drug-related TEAEs (15-min infusion: 6 [23.1%]; bolus: 4 [16.7%]). No patients discontinued due to TEAEs, and no deaths occurred.

Significance: IV BRV (up to 200 mg/day) was well tolerated in patients ≥1 month to <16 years of age, regardless of whether BRV was administered as 15-min infusion or bolus. No unexpected safety or pharmacokinetic differences were observed between patients receiving 15-min infusions or bolus, and plasma concentrations were in the expected range. Safety results were consistent with the known safety profile of oral BRV, with no new safety concerns identified.

Keywords: antiseizure medication; brivaracetam; epilepsy; focal seizure; pediatric.

Conflict of interest statement

M.K.F., H.K., and A.F. report no conflicts of interest. A.B., W.K., D.M., E.W., and J.‐P.E. are employees of UCB Pharma. A.B., D.M., and J.‐P.E. also receive UCB Pharma stocks. G.D.J. is contracted by UCB Pharma for statistical services.

© 2022 UBC Biosciences GmbH. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1

Trial design and treatment schedule. aTreatment initiated with oral BRV 2 mg/kg/day (not exceeding 100 mg/day for body weights ≥50 kg); could have been adjusted to maximum dose of 4 mg/kg/day (not exceeding 200 mg/day for body weights ≥50 kg). bPatients who received at least four BRV doses during IOB or IV PK period who did not plan to continue BRV or discontinued BRV entered this period; those who received less than four BRV doses may have entered this period at the discretion of the investigator. c50 mg/day if body weight ≥50 kg. dOnly patients who down‐titrated had a safety (BRV‐free) period. BRV, brivaracetam; h, hour; IOB, initiating oral brivaracetam; IV, intravenous; PK, pharmacokinetic; q12h, every 12 h

FIGURE 2

Patient flow diagram. AE, adverse event; IV, intravenous; PK, pharmacokinetic

FIGURE 3

BRV plasma concentrations at Visit 3 by (A) age cohort, (B) administration, and (C) patient group (IV PK period) (PK‐PPS). Values below the limit of quantification were replaced by the value of the limit of quantification in all calculations. Data are only displayed if at least two‐thirds of the concentrations were quantified at the respective timepoint. Boxplot whiskers extend out to Q3+1.5*IQR and Q1−1.5*IQR. BRV, brivaracetam; IIB, initiating intravenous brivaracetam; IOB, initiating oral brivaracetam; IQR, interquartile range; IV, intravenous; PK, pharmacokinetic; PK‐PPS, pharmacokinetic per‐protocol set; Q1, 25th percentile; Q3, 75th percentile; RxB, prescribed brivaracetam