Abstracts

Rationale: Brivaracetam (BRV), a potential adjunctive treatment for adults with partial-onset epilepsy, may be co-administered with carbamazepine (CBZ), a commonly used antiepileptic drug. When used concomitantly, BRV induces a dose-related increase in the active metabolite CBZ-10,11-epoxide (CBZ-E) through inhibition of epoxide hydrolase; the clinical significance of this increase is unclear. This analysis assesses the association, if any, between BRV-induced elevated CBZ-E and toxicity.Methods: Data were evaluated from three Phase 3, fixed-dose, placebo-controlled studies of BRV 5–200 mg/day (NCT00490035; NCT00464269; NCT01261325) focusing on treatment-emergent adverse events (TEAEs) and CBZ and CBZ-E plasma concentrations. Analyses were also conducted on serious adverse events (SAEs) in all treated patients, including ongoing long-term follow-up studies. Search criteria included MedDRA preferred terms of TEAEs recognized as being potentially associated with CBZ-E toxicity (ataxia, diplopia, dizziness, nystagmus, somnolence) and those reporting diagnoses of toxicity (accidental overdose, accidental poisoning, overdose, poisoning, toxicity to various agents). Logistic regression analysis evaluated the association between CBZ-E levels and TEAEs, using plasma concentrations and mean CBZ-E/CBZ ratio to control for normal variability of CBZ levels over time.Results: Data from 1558 patients were retrieved from the clinical database of the three studies. Among placebo- (n=459) and BRV-treated (n=1099) patients, 184 (40.1%) and 449 (40.9%) received concomitant CBZ, respectively, and were included in the analysis. Demographic characteristics were comparable in patients with (CBZ+ group) and without (CBZ– group) concomitant CBZ usage, with a mean age of ~39 years and a ~50/50 split between males and females across both groups. Among BRV-treated patients, completion rates were similar in the CBZ+ (92.2%) and CBZ– (89.1%) groups, as was the incidence of TEAEs of interest (CBZ+ 22.7% vs CBZ– 22.6%; Table). However, SAEs and discontinuations due to TEAEs were more frequent in the CBZ– group than in the CBZ+ group (3.4% vs 1.1% and 8.6% vs 2.9%, respectively). Similar rates of TEAEs were seen in BRV-treated patients receiving CBZ ≤1200 mg (24.5%) vs >1200 mg (28.6%). Plasma concentrations of CBZ and CBZ-E were available for 97% of patients. The odds ratio (OR) for experiencing TEAEs of interest for all patients with a CBZ-E ratio during the 12-week treatment period was 0.94 (95% CI 0.81, 1.07; p=0.354). For BRV, OR was 0.88 (95% CI 0.74, 1.03; p=0.112). In all treated patients (N=3776), five SAEs of interest (three with reported BRV causality) were reported in long-term follow-up studies; all patients recovered. It was not possible to determine if symptoms were due to CBZ-E as levels were unavailable.Conclusions: Analysis of data from the Phase 3 studies of BRV do not support an association between CBZ-E levels and symptoms of toxicity. Currently, there is no evidence to suggest that BRV dose adjustment is required when used concomitantly with CBZ. UCB supported.