A multicenter retrospective study to investigate the association between plasma cenobamate concentration, patients' phenotypic characteristics, and the effect of co-administered antiepileptic medications on seizure management

Francesca Felicia Operto^1*Viviana Izzo^2,3Giovanni Assenza^4,5Anna Chiara Balsamo⁶Laura Canafoglia⁷Emanuele Cerulli Irelli⁸Albino Coglianese^2,9Carlo Di Bonaventura⁸Antonio Gambardella^10,11Claudio Liguori^12,13Grazia Maria Giovanna Pastorino¹⁰Marianna Pezzella¹⁴Rosaria Renna¹⁵Ilaria Sammarra¹⁶Mario Tombini^17,18Mariana Fernandes¹²Matteo Antonucci¹²Bruno Charlier^2,3

• ¹Department of Science of Health, School of Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy., Catanzaro, Italy
• ²Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi, Italy
• ³Operative Unit of Clinical Pharmacology, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy
• ⁴Research Unit of neurology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
• ⁵Operative Research Unit of Neurology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy
• ⁶Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy
• ⁷Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologio Carlo Besta, Milan, Italy
• ⁸Department of Human Neurosciences, Sapienza University, Rome, Italy
• ⁹Graduate School in Clinical Pathology and Clinical Biochemistry, University of Salerno., Salerno, Italy
• ¹⁰Department of Science of Health, School of Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy
• ¹¹Neurologic Clinic, Magna Græcia University of Catanzaro, Catanzaro, Italy
• ¹²Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
• ¹³Neurology Unit, University Hospital of Rome Tor Vergata, Rome, Italy
• ¹⁴Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli, Naples, Italy
• ¹⁵Neurological Clinic and Stroke Unit, AORN San Pio, Benevento, Italy
• ¹⁶Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
• ¹⁷Research Unit of Neurology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
• ¹⁸Operative Research Unit of Neurology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy

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 nonlinear 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. A clinical response, defined as ≥50% reduction in seizures, was achieved in 26/53 (49%) subjects. Among responders, 53.8% (14/26) achieved response on ≤100 mg/day, with CNBp of 0.5–17.6 µg/mL (median ~5–6 µg/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. These findings suggest that CNB may achieve meaningful seizure control even at low doses, with variability in plasma concentrations largely influenced by concomitant medications and, to a lesser extent, by individual characteristics. Although limited by sample size, our results highlight the value of therapeutic drug monitoring and individualized titration to optimize CNB therapy in drug-resistant focal epilepsy.