Abstracts

Rationale: Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A approved in the EU, USA, and Canada as adjunctive therapy for focal (partial-onset) seizures in adults (?-16 years) with epilepsy. BRV is available as oral tablets, oral solution, and an intravenous (IV) formulation, for administration at the same dosage and frequency as oral BRV. This abstract reports the safety and tolerability of IV BRV. During BRV clinical development, 177 participants (healthy volunteers and patients with epilepsy) received IV BRV in the clinical pharmacology studies N01256 and EP0007 (NCT01796899), or a Phase III study N01258 (NCT01405508). We report pooled safety/tolerability findings from 153 participants receiving BRV 25?"150 mg doses. The therapeutic range of BRV is 25?"100 mg twice daily (50?'200 mg /day). Methods: In N01256, a dose-escalation crossover study, 24 healthy volunteers received IV BRV as a 15-minute infusion or 50 mg/min bolus (25, 50, 100, or 150 mg single doses (n=6 in all groups). In EP0007, a bioequivalence five-way crossover study, 25 healthy volunteers received IV BRV 100 mg as a single 2-minute bolus injection or oral tablets. In N01258, a four-arm parallel-group study, 104 patients received 7 days of BRV oral tablets 200 mg/day or placebo, and then 4.5 days of IV BRV 100 mg twice daily either as a 2-minute bolus or 15-minute infusion for a total of nine doses. Treatment-emergent adverse event (TEAE) data were pooled. Data for patients with epilepsy were also reported separately. Results: Data reported are for IV BRV 25?"150 mg (n=153). Most frequent TEAEs were somnolence 30.1%, dizziness 15.7%, fatigue 15.0%, headache 7.2%, dysgeusia 6.5%, euphoric mood 3.9%, feeling drunk 3.9%, and infusion-site pain 3.3%. Of these, in the 100 mg IV group TEAE incidence was driven by patients (n=104) vs healthy volunteers (n=31): somnolence n=23 vs n=8, dizziness 8 vs 11, fatigue 5 vs 9, headache 7 vs 3, dysgeusia 4 vs 4, euphoric mood 1 vs 3, feeling drunk 0 vs 4, and infusion-site pain 5 vs 0. Most TEAEs were mild or moderate. Infusion-site pain was specific to administration route; other administration-site conditions in ?-2 patients were injection-site extravasion (2.0%); injection-site erythema and pain, catheter-site inflammation, and vessel puncture-site hematoma (all 1.3%). Dysgeusia and euphoric mood were more common with IV vs oral administration; euphoric mood occurred mostly in healthy volunteers. Conclusions: IV BRV appeared to be well tolerated, with an AE profile consistent with oral administration except for route-specific injection-site reactions, dysgeusia, and euphoric mood. However, the interpretation of these data was complicated by the difficulty of pooling disparate studies involving healthy volunteers and epilepsy patients with heterogeneous medical histories and concomitant antiepileptic drug use. Specific monitoring of TEAEs is not required for the IV formulation; however, further clinical trials or real-world experience are needed to understand potential clinical impact. Funding: UCB Pharma funded