Critical Appraisal of Cenobamate as Adjunctive Treatment of Focal Seizures in Adults

Gaetano Zaccara,1 Simona Lattanzi,2 Antonio Leo,3 Emilio Russo3 1Regional Health Agency of Tuscany, Firenze, Italy; 2Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy; 3Science of Health Department, University Magna Grecia of Catanzaro, Catanzaro, 88100, ItalyCorrespondence: Gaetano ZaccaraRegional Health Agency of Tuscany, via Pietro Dazzi 1, Firenze, 50141, ItalyTel +39 055 2336851Email gaetanozaccara@yahoo.itAbstract: Cenobamate (CNB) is the latest antiseizure medication (ASM) authorized for the treatment of focal-onset seizures in adults. Although the precise mechanism of action of CNB is not yet fully understood, this drug inhibits the persistent, rather than transient, voltage-gated sodium channel currents and is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, differently from benzodiazepines. CNB has a non-linear pharmacokinetic with a terminal half-life range of about 50/60 hours within the therapeutic dose range, which allows once daily administration. Cenobamate inhibits cytochrome P450 (CYP) 2C19 and induces CYP3A4 and 2B6, and hence can potentially interact with ASMs (eg, phenytoin, carbamazepine and clobazam) and no-ASMs drugs. In two randomized, double-blind, placebo-controlled trials in patients with focal epilepsies, CNB has shown a particularly good efficacy with a rate of seizure freedom of about 20% during the maintenance period in participants treated with the dose of 400 mg/day. The most common treatment-emergent adverse effects include central nervous system-related symptoms, like dizziness, diplopia, somnolence, and gait disturbances. Safety issues of particular interest are severe skin reactions (drug reaction with eosinophilia and systemic symptoms) and QT shortening, which contraindicates its use in subjects with familial short QT syndrome or in combination with other QT-shortening drugs. The recommended starting dose is 12.5 mg/day, which can be gradually titrated to the target dose (200 mg/day) and further increased up to 400 mg/day. There are several aspects of CNB that need to be still addressed, including the long-term efficacy and the efficacy in patients with generalized seizures. Ongoing studies will clarify these issues. The clinical relevance of the peculiar pharmacokinetics and the pattern of drug–drug interactions also require further investigation.Keywords: cenobamate, focal seizures, antiseizure medications, drug–drug interactions, safety, efficacy