Featured Application: These findings suggest a potential application of pharmacogenetic profiling to support personalized treatment strategies in patients with drug-resistant epilepsy receiving cenobamate. In particular, CYP2C19 genotyping may help identify individuals—such as intermediate metabolizers—who could be at increased risk of adverse events when cenobamate is combined with CYP2C19-substrate antiseizure medications. This approach could inform more tailored drug selection, dose adjustments, and closer clinical monitoring during the early phases of treatment. In clinical practice, integrating pharmacogenetic data with therapeutic decision-making may improve tolerability and reduce treatment discontinuation. Although preliminary, this study supports the future development of genotype-guided algorithms combining pharmacogenetics and clinical variables to optimize antiseizure therapy. Background: Cenobamate is a novel antiseizure medication with potential interactions involving cytochrome P450 enzymes, including CYP2C19. Genetic variability in CYP2C19 may influence drug metabolism and tolerability, although its clinical relevance in cenobamate-treated patients remains unclear. Methods: We conducted a single-center retrospective study including 48 adults with drug-resistant epilepsy treated with cenobamate. Patients were stratified by concomitant use of CYP2C19-substrate ASMs (patients with CYP2C19 substrates vs. patients without CYP2C19 substrates). CYP2C19 genotype was classified into metabolizer phenotypes. Adverse events (AEs) were categorized as potentially CYP-mediated or likely unrelated to CYP-mediated pharmacokinetic mechanisms based on clinical assessment, temporal association, and known pharmacological interaction profiles. Associations were explored using descriptive statistics and regression models. Results: Overall, 58.3% of patients received CYP2C19-substrate ASMs. AEs were more frequent among patients with CYP2C19 substrates (71.4% vs. 20.0%; p = 0.001), with potentially CYP-mediated AEs observed only in this group (32.1% vs. 0%; p < 0.001). Intermediate metabolizers showed a higher proportion of potentially CYP-mediated AEs (87.5%; p < 0.001). This pattern was not observed in patients without CYP2C19 substrates. Regression analyses suggested increased risk in intermediate metabolizers, although estimates were imprecise and should be considered exploratory. Conclusions: An exploratory association between CYP2C19 variability and AE occurrence was observed in patients treated with cenobamate combined mainly with clobazam and other CYP2C19-substrate ASMs. Intermediate metabolizers may represent a higher-risk subgroup, but these preliminary findings require prospective confirmation with pharmacokinetic monitoring.
Exploring the Potential Role of CYP2C19 Genetic Variability in Cenobamate Treatment
Falcicchio G.;Delmonte V.;Introna A.;Mariggio M. A.;Pafundi M.;Perrone M.;Vinella A.;
2026-01-01
Abstract
Featured Application: These findings suggest a potential application of pharmacogenetic profiling to support personalized treatment strategies in patients with drug-resistant epilepsy receiving cenobamate. In particular, CYP2C19 genotyping may help identify individuals—such as intermediate metabolizers—who could be at increased risk of adverse events when cenobamate is combined with CYP2C19-substrate antiseizure medications. This approach could inform more tailored drug selection, dose adjustments, and closer clinical monitoring during the early phases of treatment. In clinical practice, integrating pharmacogenetic data with therapeutic decision-making may improve tolerability and reduce treatment discontinuation. Although preliminary, this study supports the future development of genotype-guided algorithms combining pharmacogenetics and clinical variables to optimize antiseizure therapy. Background: Cenobamate is a novel antiseizure medication with potential interactions involving cytochrome P450 enzymes, including CYP2C19. Genetic variability in CYP2C19 may influence drug metabolism and tolerability, although its clinical relevance in cenobamate-treated patients remains unclear. Methods: We conducted a single-center retrospective study including 48 adults with drug-resistant epilepsy treated with cenobamate. Patients were stratified by concomitant use of CYP2C19-substrate ASMs (patients with CYP2C19 substrates vs. patients without CYP2C19 substrates). CYP2C19 genotype was classified into metabolizer phenotypes. Adverse events (AEs) were categorized as potentially CYP-mediated or likely unrelated to CYP-mediated pharmacokinetic mechanisms based on clinical assessment, temporal association, and known pharmacological interaction profiles. Associations were explored using descriptive statistics and regression models. Results: Overall, 58.3% of patients received CYP2C19-substrate ASMs. AEs were more frequent among patients with CYP2C19 substrates (71.4% vs. 20.0%; p = 0.001), with potentially CYP-mediated AEs observed only in this group (32.1% vs. 0%; p < 0.001). Intermediate metabolizers showed a higher proportion of potentially CYP-mediated AEs (87.5%; p < 0.001). This pattern was not observed in patients without CYP2C19 substrates. Regression analyses suggested increased risk in intermediate metabolizers, although estimates were imprecise and should be considered exploratory. Conclusions: An exploratory association between CYP2C19 variability and AE occurrence was observed in patients treated with cenobamate combined mainly with clobazam and other CYP2C19-substrate ASMs. Intermediate metabolizers may represent a higher-risk subgroup, but these preliminary findings require prospective confirmation with pharmacokinetic monitoring.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
