Abstracts

Rationale: Brivaracetam (BRV) has shown promising efficacy and safety as adjunctive therapy in adults with epilepsy. Here we present the findings from the first study of BRV administered as oral solution in infants and children with epilepsy.Methods: This was a Phase 2a, open-label, single-arm, multicenter study (NCT00422422; N01263). Patients were aged 1 month <16 years with localized, generalized, or undetermined as to focal or generalized seizures and taking 1 3 concomitant antiepileptic drugs (excluding levetiracetam). The study comprised: 1-week prospective baseline period; 3-week evaluation period followed by entry to long-term follow-up study, or 2-week down-titration period, and 2-week safety period. During the evaluation period, dose was titrated based on age. Patients aged 8 years received 0.4, 0.8, and 1.6mg/kg bid at Weeks 1, 2, and 3, respectively; patients aged <8 years received 0.5, 1.0, and 2.0mg/kg bid at weeks 1, 2, and 3, respectively. The dosing rationale was estimated on the basis of physiologically-based pharmacokinetic predictions. Up to three plasma samples were obtained at each dose step for BRV determination. Safety variables included adverse events (AEs), laboratory tests, electrocardiograms, and vital signs. Analyses were performed on the safety population.Results: 100 patients entered; 99 comprised the safety population (mean age 6.3 years; 51.5% female; 50.5% focal epilepsy). 90 (90.0%) completed the study, 10 (10.0%) discontinued (AEs, n=6; lack of efficacy, n=1, protocol violation, n=1; consent withdrawn, n=2). Median duration of study medication exposure was 22 days (range 1 29 days) with 81 patients (81.8%) evaluated for 3 4 weeks. Overall, 66 (66.7%) patients reported 1 treatment-emergent AE (TEAE) and 32 (32.3%) reported 1 drug-related TEAE (Table 1). The most common TEAEs were convulsion (10.1%), irritability, pyrexia, and somnolence (all 8.1%). Incidence of patients reporting TEAEs was greater in patients aged 1 month <2 years (80.0%) than those aged 2 <12 years (60.8%) or 12 <16 years (61.1%); however, drug-related TEAEs were less frequent in patients aged 1 month <2 years (16.7%) than those aged 2 <12 years (41.2%) or 12 <16 years (33.3%). The most common drug-related TEAEs were somnolence (7.1%) and decreased appetite (6.1%). The overall percentage of patients reporting 1 TEAE during each up-titration step was similar (Week 1, 39.6%; Week 2, 39.8%; Week 3, 26.8%). 8.1% patients reported 1 treatment-emergent serious AE (SAE), the most common was convulsion (4.0%). No deaths were reported. No clinically meaningful changes in laboratory tests, body weight, or vital signs were observed. Average trough plasma concentrations at the highest dose were 0.8, 0.9, and 1.1 g/mL in 1 month <2, 2 <12 and 12 <16 year groups, respectively.Conclusions: Treatment of pediatric patients with BRV (oral solution) was generally well-tolerated, and supports the further development of BRV as adjunctive therapy for pediatric patients with epilepsy.