Dose-dependent Effects of Cenobamate on Brivaracetam Pharmacokinetics: A Retrospective Cohort Study

Background: Cenobamate is a novel antiseizure medication that inhibits cytochrome P450 2C19 (CYP2C19), which is involved in brivaracetam metabolism. Therefore, a pharmacokinetic interaction is assumed. In this study, the authors investigated the effects of cenobamate comedication on serum brivaracetam concentrations. Methods: In this retrospective, single-center study, routinely collected serum concentrations of brivaracetam were analyzed in patients receiving brivaracetam concomitantly with cenobamate (06/2021–10/2024) and in those treated with brivaracetam without cenobamate (02/2016–03/2017). Statistical analyses were performed using generalized estimating equations, accounting for additional factors with a potential effect on serum brivaracetam concentrations (eg, enzyme-inducing comedication). Results: In total, 891 samples from 213 patients were analyzed. A biphasic drug–drug interaction was observed: at low cenobamate doses (12.5–50 mg/d), an increase in brivaracetam concentrations was observed (+32%, P = 0.001) compared with that in patients without cenobamate comedication. By contrast, high cenobamate doses (250–450 mg/d) were associated with a significant decrease in brivaracetam concentrations (−21%, P < 0.001). Conclusions: These results demonstrate that cenobamate affects brivaracetam pharmacokinetics in a biphasic, dose-dependent manner. Furthermore, divergent effects were observed at low cenobamate doses (≤50 mg/d) versus high (≥250 mg/d) cenobamate doses. These findings highlight the need for prospective studies that define the clinical relevance of this interaction better.