Efficacy and safety of cenobamate-based combination therapy in drug-resistant epilepsy: Secondary analysis by mechanisms of action of concomitant antiseizure medications

INTRODUCTION: In a secondary analysis of a cohort of 475 adults with drug-resistant epilepsy treated with adjunctive cenobamate, we assessed whether treatment outcomes were influenced by concomitant antiseizure medication class and cenobamate dose. MATERIALS AND METHODS: Concomitant antiseizure medications (ASMs) were grouped as sodium channel blockers (SCBs), SV2A ligands, valproate, carbonic anhydrase inhibitors, or GABA analogs. Efficacy and safety outcomes were analyzed using multivariate logistic regression, adjusting for confounders. RESULTS: Baseline use of valproate was associated with higher odds of achieving ≥50 % seizure reduction and seizure freedom, whereas SCB co-therapy was associated with lower odds of seizure freedom. At the final follow-up, these efficacy differences largely disappeared, except that SCB use modestly favored ≥50 % response. SCB co-medication was associated with a decreased risk of somnolence, while the presence of an SV2A ligands, valproate, or carbonic anhydrase inhibitors was correlated with lower treatment discontinuation rates. Cenobamate dose showed no significant association with achieving ≥50 % response, seizure freedom, or overall AE occurrence, reflecting the pragmatic character of the studied cohort. CONCLUSION: Cenobamate demonstrated optimal efficacy when combined with valproate and broad-spectrum agents, and suboptimal efficacy when coadministered with SCB. Substantial seizure improvements were often achieved at moderate doses of cenobamate, underscoring the value of individualized titration and comedication management.