Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Cenobamate: A Review of its Pharmacological Properties, Clinical Efficacy and Tolerability Profile in the Treatment of Epilepsy

Author(s): Maria Antonietta Barbieri*, Emilio Perucca, Edoardo Spina, Paola Rota and Valentina Franco

Volume 22, Issue 3, 2023

Published on: 11 April, 2022

Page: [394 - 403] Pages: 10

DOI: 10.2174/1871527321666220113110044

open access plus

Abstract

Cenobamate is a novel antiseizure medication (ASM) commercially available in Europe and in the U.S. for the treatment of focal seizures in adults. The mechanisms responsible for its antiseizure activity include enhancement of the inactivated state of voltage-gated sodium channels with blockade of the persistent sodium current and positive allosteric modulation of GABAA receptors at a non-benzodiazepine binding site. Cenobamate has a high oral bioavailability that is not influenced by food intake. The terminal half-life is 50-60 hours, allowing for once-daily dosing. Cenobamate is a CYP2C19 inhibitor and an inducer of CYP3A4 and CYP2B6, and consequently, it can cause a number of drug-drug interactions. Efficacy and safety have been evaluated in two randomized, double-blind, placebo-controlled adjunctive therapy trials in adults with focal seizures. In both trials, cenobamate decreased significantly the frequency of focal seizures, with relatively high seizure freedom rates. Adverse events most commonly reported in double-blind trials included dizziness, somnolence, headache, fatigue, and diplopia. The occurrence of three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) during early clinical development led to the conduction of a Phase 3 open-label long-term safety study in a total of 1339 patients. In this study, no serious idiosyncratic adverse reactions were observed using a start-low and go-slow approach. Further studies are required to determine whether the clinical activity profile of cenobamate extends to protection against other seizure types and to evaluate its efficacy and safety profile in special patient groups such as infants, children, the elderly, and patients with comorbid conditions.

Keywords: Cenobamate, epilepsy, pharmacology, pharmacokinetics, efficacy, safety.

« Previous Next »
[1]
World Health Organization. Epilepsy. A Public Health Imperative. Available from:https://www.who.int/publications/i/item/epilepsy-a-public-health-imperative
[2]
Tomson T, Beghi E, Sundqvist A, Johannessen SI. Medical risks in epilepsy: A review with focus on physical injuries, mortality, traffic accidents and their prevention. Epilepsy Res 2004; 60(1): 1-16.
[http://dx.doi.org/10.1016/j.eplepsyres.2004.05.004] [PMID: 15279865]
[3]
Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort study. JAMA Neurol 2018; 75(3): 279-86.
[http://dx.doi.org/10.1001/jamaneurol.2017.3949] [PMID: 29279892]
[4]
Perucca E, Brodie MJ, Kwan P, Tomson T. 30 years of second- generation antiseizure medications: Impact and future perspectives. Lancet Neurol 2020; 19(6): 544-56.
[http://dx.doi.org/10.1016/S1474-4422(20)30035-1] [PMID: 32109411]
[5]
Fattore C, Perucca E. Novel medications for epilepsy. Drugs 2011; 71(16): 2151-78.
[http://dx.doi.org/10.2165/11594640-000000000-00000] [PMID: 22035515]
[6]
XCOPRI® Prescribing Information. SK Life Science Inc., Paramus, NJ. Available from:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212839s000lbl.pdf(accessed August 5, 2021).
[7]
Ontozry®, Summary of Product Characteristics. Arvelle Therapeutics, Inc., Amsterdam. Available from:https://www.ema.europa.eu/en/documents/product-information/ontozry-epar-product-information_en.pdf(accessed August 5, 2021).
[8]
Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology 2020; 94(22): e2311-22.
[http://dx.doi.org/10.1212/WNL.0000000000009530] [PMID: 32409485]
[9]
Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: A multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol 2020; 19(1): 38-48.
[http://dx.doi.org/10.1016/S1474-4422(19)30399-0] [PMID: 31734103]
[10]
Sperling MR, Klein P, Aboumatar S, et al. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study. Epilepsia 2020; 61(6): 1099-108.
[http://dx.doi.org/10.1111/epi.16525] [PMID: 32396252]
[11]
Roberti R, De Caro C, Iannone LF, Zaccara G, Lattanzi S, Russo E. Pharmacology of cenobamate: Mechanism of action, pharmacokinetics, drug-drug interactions and tolerability. CNS Drugs 2021; 35(6): 609-18.
[http://dx.doi.org/10.1007/s40263-021-00819-8] [PMID: 33993416]
[12]
Lattanzi S, Trinka E, Zaccara G, et al. Adjunctive cenobamate for focal-onset seizures in adults: A systematic review and meta-analysis. CNS Drugs 2020; 34(11): 1105-20.
[http://dx.doi.org/10.1007/s40263-020-00759-9] [PMID: 32851590]
[13]
Guignet M, Campbell A, White HS. Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action? Epilepsia 2020; 61(11): 2329-39.
[http://dx.doi.org/10.1111/epi.16718] [PMID: 33063849]
[14]
Ontozry, Public Assessment Report. Available from: https://www.ema.europa.eu/en/documents/assessment-report/ontozry-epar-public-assessment-report_.pdf (accessed August 5, 2021).
[15]
Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development. Epilepsia 2020; 61(11): 2365-85.
[http://dx.doi.org/10.1111/epi.16726] [PMID: 33165915]
[16]
Melnick S, Shin H, Roucard C, et al. Cenobamate (YKP3089) dose-dependently reduced spike-and-wave discharges in the genetic absence epilepsy rats from strasbourg (GAERS) animal model. Neuroscience 2019; October 19-23, 2019; Chicago, IL. 2019. Available from: https://www.abstractsonline.com/pp8/#!/7883/presentation/69880 (accessed November 3, 2021).
[17]
Kasteleijn-Nolst Trenite DGA, DiVentura BD, Pollard JR, Krauss GL, Mizne S, French JA. Suppression of the photoparoxysmal response in photosensitive epilepsy with cenobamate (YKP3089). Neurology 2019; 93(6): e559-67.
[http://dx.doi.org/10.1212/WNL.0000000000007894] [PMID: 31292226]
[18]
Nakamura M, Cho JH, Shin H, Jang IS. Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons. Eur J Pharmacol 2019; 855: 175-82.
[http://dx.doi.org/10.1016/j.ejphar.2019.05.007] [PMID: 31063770]
[19]
Sharma R, Nakamura M, Neupane C, et al. Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate. Eur J Pharmacol 2020; 879: 173117.
[http://dx.doi.org/10.1016/j.ejphar.2020.173117] [PMID: 32325146]
[20]
Drug Enforcement Administration (U.S). Schedules of Controlled Substances: Placement of Cenobamate in Schedule V. Fed. Regist. 2020; 85(162). https://www.deadiversion.usdoj.gov/fed_regs/rules/2020/fr0820.htm
[21]
Vernillet L, Greene SA, Kim HW, Melnick SM, Glenn K. Mass balance, metabolism, and excretion of cenobamate, a new antiepileptic drug, after a single oral administration in healthy male subjects. Eur J Drug Metab Pharmacokinet 2020; 45(4): 513-22.
[http://dx.doi.org/10.1007/s13318-020-00615-7] [PMID: 32301064]
[22]
Vernillet L, Greene SA, Kamin M. Pharmacokinetics of cenobamate: Results from single and multiple oral ascending-dose studies in healthy subjects. Clin Pharmacol Drug Dev 2020; 9(4): 428-43.
[http://dx.doi.org/10.1002/cpdd.769] [PMID: 32087001]
[23]
Greene S, Orlinski L, Streicher C, Vernillet L. The pharmacokinetics of cenobamate in special populations (P1.5-034). Neurology 2019; 92(15) (Suppl.): 5-034.
[24]
Vernillet L, Kamin M. Drug–drug interactions between cenobamate and other antiepileptic drugs: results from phase I studies with carbamazepine, phenobarbital, phenytoin, and divalproex sodium. Clin Pharmacol Ther 2018; 103 (Suppl. 1): S91. [abstract no. PII-135].
[25]
Krauss GL, Klein P, Brandt C, et al. Safety of adjunctive treatment with cenobamate in patients with uncontrolled focal seizures - Authors’ reply. Lancet Neurol 2020; 19(4): 288-9.
[http://dx.doi.org/10.1016/S1474-4422(20)30077-6] [PMID: 32199090]
[26]
Mudigoudar B, Wheless J. Safety of adjunctive treatment with cenobamate in patients with uncontrolled focal seizures. Lancet Neurol 2020; 19(4): 288.
[http://dx.doi.org/10.1016/S1474-4422(20)30069-7] [PMID: 32199091]
[27]
Brodie MJ, Covanis A, Gil-Nagel A, et al. Antiepileptic drug therapy: Does mechanism of action matter? Epilepsy Behav 2011; 21(4): 331-41.
[http://dx.doi.org/10.1016/j.yebeh.2011.05.025] [PMID: 21763207]
[28]
Steinhoff BJ, Rosenfeld WE, Serratosa JM, et al. Practical guidance for the management of adults receiving adjunctive cenobamate for the treatment of focal epilepsy-expert opinion. Epilepsy Behav 2021; 123: 108270.
[http://dx.doi.org/10.1016/j.yebeh.2021.108270] [PMID: 34509033]
[29]
Rosenfeld WE, Abou-Khalil B, Aboumatar S, et al. Post-hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications. Epilepsia 2021; 62(12): 3016-28.
[http://dx.doi.org/10.1111/epi.17092] [PMID: 34633074]
[30]
French JA, Chung SS, Krauss GL, et al. Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study. Epilepsia 2021; 62(9): 2142-50.
[http://dx.doi.org/10.1111/epi.17007] [PMID: 34254673]
[31]
Klein P, Krauss G, Aboumatar S, Kamin M. Long-term efficacy and safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study (1008). Neurology 2020; 94(15) (Suppl.): 1008.
[32]
Sperling MR, Abou-Khalil B, Aboumatar S, et al. Efficacy of cenobamate for uncontrolled focal seizures: Post-hoc analysis of a Phase 3, multicenter, open-label study. Epilepsia 2021; 62(12): 3005-15.
[http://dx.doi.org/10.1111/epi.17091] [PMID: 34633084]
[33]
Rosenfeld WE, Nisman A, Ferrari L. Efficacy of adjunctive cenobamate based on number of concomitant antiseizure medications, seizure frequency, and epilepsy duration at baseline: A post-hoc analysis of a randomized clinical study. Epilepsy Res 2021; 172: 106592.
[http://dx.doi.org/10.1016/j.eplepsyres.2021.106592] [PMID: 33662894]
[34]
Strzelczyk A, Mann C, Willems LM, Rosenow F, Bauer S. Cenobamate for the treatment of focal epilepsies. Expert Opin Pharmacother 2020; 21(18): 2215-23.
[http://dx.doi.org/10.1080/14656566.2020.1803830] [PMID: 32812825]
[35]
Tomson T, Battino D, Craig J, et al. ILAE Commission on Therapeutic Strategies. Pregnancy registries: Differences, similarities, and possible harmonization. Epilepsia 2010; 51(5): 909-15.
[http://dx.doi.org/10.1111/j.1528-1167.2010.02525.x] [PMID: 20196792]

Rights & Permissions Print Cite
Article Metrics
15
© 2024 Bentham Science Publishers | Privacy Policy