Rapidity of CNS Effect on Photoparoxysmal Response for Brivaracetam vs. Levetiracetam: A Randomized, Double-blind, Crossover Trial in Photosensitive Epilepsy Patients

Abstract

Introduction Both levetiracetam (LEV) and brivaracetam (BRV) eliminate the electroencephalogram photoparoxysmal response (PPR) in the human phase IIa photosensitivity model of epilepsy. The physiochemical properties of BRV differ from those of LEV, having higher potency and lipophilicity plus 10-to 15-fold greater affinity for synaptic vesicle glycoprotein 2A. Objective We compared the rapidity of the effects of both drugs in the central nervous system (CNS) of patients with photosensitive epilepsy using time to PPR elimination post-intravenous infusion as a pharmacodynamic endpoint. Methods Using a randomized, double-blind, two-period, balanced, crossover design, we tested patients with photosensitive epilepsy with equipotent milligram doses of intravenous LEV 1500 mg versus BRV 100 mg post-15-min intravenous infusion (part 1) and post-5-min intravenous infusion (part 2, same doses). Eight patients per part were deemed sufficient with 80% power to determine a 70% reduction for intravenous BRV:LEV intrapatient time ratio to PPR elimination, with a 0.05 two-sided significance level. Plasma antiseizure medicine concentrations were measured using liquid chromatography/ mass spectrometry. Results Nine patients [six women; mean age 27.8 years (range 18-42)] completed the study; seven of these participated in both parts 1 and 2. In 31 of 32 instances, patients experienced PPR elimination. In mixed-effects model time analysis, BRV eliminated PPRs more quickly than did LEV (median 2 vs. 7.5 min, respectively). However, no statistically significant difference in BRV:LEV time ratio to PPR elimination was observed for two of our multiple primary outcomes: for the 15-min infusion alone (p = 0.22) or the 5-min infusion alone (p = 0.11). However, BRV was faster when we excluded an outlier patient in part 1 (p = 0.0016). For our remaining primary outcome, parts 1 and 2 data combined, the median intrapatient BRV:LEV time ratio was 0.39 [95% confidence interval (CI) 0.16-0.91], i.e., PPR elimination was 61% faster with BRV, p = 0.039. PPR was completely eliminated in ≤ 2 min in 11 patients with BRV and in four patients with LEV. No period or carryover effects were seen. No serious or severe adverse effects occurred. At PPR elimination (n = 16), median plasma [BRV] was 250 ng/mL (range 30-4100) and median plasma [LEV] was 28.35 μg/mL (range 1-86.7). Conclusion Outcome studies directly comparing LEV and BRV are needed to define the clinical utility of the response with BRV, which was several minutes faster than that with LEV. Clinical trials ClinTrials.gov Identifier = NCT03580707; registered 07-09-18

Visually sensitive seizures: An updated review by the Epilepsy Foundation

“…Cenobamate 281 is the most recently US Food and Drug Administration (FDA)approved ASM tested in photosensitive subjects. The PM can be tailored to the relevant questions, for example, efficacy against status epilepticus or seizure clusters, as shown in the comparative time to PPR abolition after intravenous infusion of levetiracetam and brivaracetam 282 or inhalation of alprazolam 283 …”

Intravenous Brivaracetam in the Management of Acute Seizures in the Hospital Setting: A Scoping Review

“…In a prospective, randomized, double-blind, crossover trial in 9 patients with photosensitive epilepsy in a hospital comprehensive epilepsy care center, IV BRV (100 mg 5- or 15-min infusion) eliminated the electroencephalographic photoparoxysmal response faster than IV LEV (median 2 vs. 7.5 min, respectively). 55 When data from the 5- and 15-min IV BRV infusions were combined, photoparoxysmal response elimination was 61% faster with BRV ( P = 0.039).…”

“… 64 IV BRV acts fast, with 100 mg 2-min bolus achieving a t max in approximately 5 min, 45 and suppression of epileptiform activity on EEG in a median of 2 min in patients with photosensitive epilepsy. 55 This translates to the rapid response observed with IV BRV. In numerous studies, resolution of status epilepticus or NCSE was observed directly by clinical observation and EEG within minutes of administration of IV BRV treatment.…”

Diagnosing nonconvulsive status epilepticus: Defining electroencephalographic and clinical response to diagnostic intravenous antiseizure medication trials

“…The other ASMs reach sufficient CNS levels within 15 min or faster. [12][13][14] Only if there has been no response on EEG, and the patient tolerated the IV ASM well, should the rest of the full dose of a non-BDZ be administered. Then, another 30-60 min should be allowed to elapse after the administration of the full dose of a non-BDZ as a diagnostic IV ASM trial before switching to the next medication.…”