{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T20:24:18Z","timestamp":1770495858177,"version":"3.49.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Cenobamate (CNB) is a novel antiseizure medication (ASM) approved as an add-on therapy for drug-resistant focal onset seizures. Although its mechanism of action is not fully understood, CNB enhances inhibitory GABAergic transmission and blocks voltage-gated sodium channels. Its non-linear pharmacokinetics and strong modulation of cytochrome P450 enzymes may significantly affect the metabolism of co-administered ASMs, posing important challenges for polytherapy management. This retrospective study, complemented by prospective follow-up evaluations, aimed at elucidating, in a cohort of subjects enrolled in an Italian multicenter study, the following: i) the CNB dose associated with clinical response; ii) inter-individual variability in CNB plasma concentrations (CNBp); iii) the potential correlation between CNBp and clinical features including age, sex and body mass index (BMI); iv) interactions between CNB and co-administered ASMs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We enrolled 53 adults with drug-resistant focal epilepsy, who started CNB with titration to 200 mg\/day, were monitored monthly, and classified as responders (\u226550% seizure reduction) or non-responders (&amp;lt;50%). In responders, plasma CNB concentration (CNBp) was measured at the time of their first documented clinical response. Multiple linear regression, including covariates such as age, sex, BMI, CNB dose, and co-administered ASMs, was applied to assess independent predictors of CNBp.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A clinical response was achieved in 26\/53 (49%) subjects. Among responders, 53.8% (14\/26) achieved response on \u2264100 mg\/day, with CNBp of 0.5\u201317.6 \u03bcg\/mL (median \u223c5\u20136 \u03bcg\/mL). There was no significant relationship between age and gender, although there was a statistically significant correlation between CNBp and BMI (p = 0.038; R2 = 0.157). In subjects co-administered benzodiazepines, zonisamide, phenobarbital, and perampanel, higher CNBp were observed; conversely, lower CNBp were linked to brivaracetam, topiramate, lamotrigine, and levetiracetam. Additionally, a modest decrease in CNBp was associated with carbamazepine, consistent with its known enzyme-inducing effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest that CNB may achieve clinically meaningful seizure control at relatively low doses, with variability in plasma concentrations largely influenced by concomitant medications and, to a lesser extent, by individual characteristics. Despite the limited sample size, our results highlight the value of therapeutic drug monitoring and individualized titration to optimize CNB therapy in drug-resistant focal epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1668382","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T05:30:14Z","timestamp":1758519014000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical predictors and concomitant antiseizure medications effects on seizure control in relation to plasma cenobamate concentration: a multicenter retrospective study"],"prefix":"10.3389","volume":"16","author":[{"given":"Francesca Felicia","family":"Operto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viviana","family":"Izzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Assenza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Chiara","family":"Balsamo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Canafoglia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Cerulli Irelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albino","family":"Coglianese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Di Bonaventura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Gambardella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Liguori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grazia Maria Giovanna","family":"Pastorino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianna","family":"Pezzella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosaria","family":"Renna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Sammarra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Tombini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Antonucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Charlier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.2174\/1871527321666220113110044","article-title":"Cenobamate: a review of its pharmacological properties, clinical efficacy and tolerability profile in the treatment of epilepsy","volume":"22","author":"Barbieri","year":"2023","journal-title":"CNSNDDT"},{"key":"B2","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S1474-4422(18)30454-X","article-title":"Global, regional, and national burden of epilepsy, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Beghi","year":"2019","journal-title":"Lancet Neurology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1571376","DOI":"10.3389\/fphar.2025.1571376","article-title":"Increase of Brivaracetam serum concentration with introduction of Cenobamate","volume":"16","author":"Bender","year":"2025","journal-title":"Front. 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