Pharmacological mechanisms and clinical research progress of cenobamate_Journal of Epilepsy

Authors：

ZHANG Juntao ^1,2 , WAN Lijun ^1,2 ,  LIU Xuewu ^1,2

1. Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250022, China;
2. Epilepsy Research Institute of Shandong University, Jinan 250022, China;

Corresponding?author：

LIU Xuewu, Email: snlxw1966@163.com

Keywords：

Cenobamate; Drug-resistant epilepsy; Focal epilepsy; Anti-seizure medication; Pharmacological mechanism

DOI：

10.7507/2096-0247.202605001

Video：

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Cenobamate is a new antiseizure medication used in recent years for adult drug-resistant focal epilepsy. Its pharmacological effects have two main features: on the one hand, it can regulate voltage-gated sodium channels, thereby reducing abnormal neuronal excitability; on the other hand, it can act as a positive allosteric modulator of γ-aminobutyric acid-A (GABA-A) receptors and enhance inhibitory neurotransmission. Several existing studies have shown that cenobamate can reduce the frequency of focal seizures and has certain advantages in improving seizure freedom rates. Its common adverse reactions are mainly central nervous system symptoms. At present, the clearest clinical position of cenobamate is still its use in adult drug-resistant focal epilepsy. Its application in children, generalized epilepsy, and special epilepsy syndromes still needs more evidence to support it. This article reviews the pharmacological mechanisms, pharmacokinetics, clinical efficacy, safety, and clinical position of cenobamate, with the aim of providing a reference for its standardized clinical use.

Citation： ZHANG Juntao, WAN Lijun, LIU Xuewu. Pharmacological mechanisms and clinical research progress of cenobamate. Journal of Epilepsy, 2026, 12(5): 409-413. doi: 10.7507/2096-0247.202605001 Copy

1.	Ding D, Zhou D, Sander JW, et al. Epilepsy in China: major progress in the past two decades[J]. Lancet Neurol, 2021, 20(4): 316-326.
2.	Ioannou P, Foster DL, Sander J W, et al. The burden of epilepsy and unmet need in people with focal seizures[J]. Brain Behav, 2022, 12(9): e2589.
3.	Ben-Menachem E, Schmitz B, K?lvi?inen R, et al. The burden of chronic drug-refractory focal onset epilepsy: Can it be prevented[J]? Epilepsy Behav, 2023, 148: 109435.
4.	Rosenfeld WE. Epilepsy medication management: Addressing common treatment barriers to adopting cenobamate and other new antiseizure medications[J]. Epilepsia, 2025, 66(Suppl 1): 38-48.
5.	Sankar R, Ferrari L, Kamin M. Exploration of the mechanism of action of cenobamate[J]. Seizure, 2026, 134: 79-85.
6.	Brigo F, Lattanzi S. Cenobamate add-on therapy for drug-resistant focal epilepsy[J]. Cochrane Database Syst Rev, 2024, 8(8): Cd014941.
7.	Kamaraj AK, Szuromi MP. Modelling dysfunction-specific interventions for seizure termination in epilepsy[J]. NPJ Syst Biol Appl, 2025, 12(1): 9.
8.	Yan R, Zhang H, Hong Z, et al. Sodium channel blockers for the treatment of focal epilepsy: A Chinese expert consensus[J]. Seizure, 2025, 127: 105-114.
9.	Nakamura M, Cho JH, Shin H, et al. Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons[J]. Eur J Pharmacol, 2019, 855: 175-182.
10.	Müller P, Draguhn A, Egorov AV. Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers[J]. Pflugers Arch, 2024, 476(10): 1445-1473.
11.	Sharma R, Nakamura M, Neupane C, et al. Positive allosteric modulation of GABA(A) receptors by a novel antiepileptic drug cenobamate[J]. Eur J Pharmacol, 2020, 879: 173117.
12.	Kim JJ, Gharpure A, Teng J, et al. Shared structural mechanisms of general anaesthetics and benzodiazepines[J]. Nature, 2020, 585(7824): 303-308.
13.	Steinhoff BJ, Georgiou D, Dietmann D, et al. Cenobamate plasma levels in patients with epilepsy: correlation with efficacy and tolerability[J]? J Clin Med, 2024, 13(10): e10256.
14.	Yang E, Sunwoo J, Huh KY, et al. Pharmacokinetics and safety of cenobamate, a novel antiseizure medication, in healthy Japanese, and an ethnic comparison with healthy non-Japanese[J]. Clin Transl Sci, 2022, 15(2): 490-500.
15.	Rissardo J , Fornari Caprara AL. Cenobamate (YKP3089) and drug-resistant epilepsy: a review of the literature[J]. Medicina (Kaunas), 2023, 59(8): 12-16.
16.	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[J]. Lancet Neurol, 2020, 19(1): 38-48.
17.	Lee SK, Yu P, Choe E, et al. A randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of adjunctive cenobamate in Asian patients with focal seizures[J]. Epilepsia, 2026, 67(2): 660-672.
18.	Yu P, Wu X, Cui L, et al. Efficacy and safety of adjunctive cenobamate in chinese participants with focal seizure[J]. Adv Ther, 2026, 43(2): 688-709.
19.	Klein P, Aboumatar S, Brandt C, et al. Long-term efficacy and safety from an open-label extension of adjunctive Cenobamate in patients with uncontrolled focal seizures[J]. Neurology, 2022, 99(10): e989-e998.
20.	Makridis KL, Kaindl AM. Real-world experience with cenobamate: a systematic review and meta-analysis[J]. Seizure, 2023, 112: 1-10.
21.	Bosak M, Podraza H, W?och-Kope? D, et al. Efficacy and safety of Cenobamate: a multicenter, retrospective evaluation of real-world clinical practice[J]. Seizure, 2025, 130: 25-31.
22.	Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures[J]. Neurology, 2020, 94(22): e2311-e2322.
23.	Sperling M R, 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[J]. Epilepsia, 2020, 61(6): 1099-1108.
24.	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[J]. Epilepsy Behav, 2021, 123: 108270.
25.	Ferrari L, Rosenfeld WE, Kamin M. A global update on cenobamate based on real-world experience in over 100 000 patients[J]. Epilepsia, 2024, 65(4): 1149-1150.
26.	Darpó B, Sager PT, Xue H, et al. A Phase 1 Clinical study evaluating the effects of cenobamate on the QT interval[J]. Clin Pharmacol Drug Dev, 2022, 11(4): 523-534.
27.	Giannelli T, Falcicchio G. Drug-induced liver injury during valproic acid and cenobamate coadministration: a direct consequence or an unforeseen event[J]? Neurol Sci, 2025, 46(3): 1419-1420.
28.	Greene SA, Kwak C, Kamin M, et al. Effect of cenobamate on the single-dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects[J]. Clin Transl Sci, 2022, 15(4): 899-911.
29.	Smith MC, Klein P, Krauss GL, et al. Dose adjustment of concomitant antiseizure medications during Cenobamate treatment: expert opinion consensus recommendations[J]. Neurol Ther, 2022, 11(4): 1705-1720.
30.	Sunaga T, Cicali B, Schmidt S, et al. Comparison of contraceptive failures associated with CYP3A4-inducing drug-drug interactions by route of hormonal contraceptive in an adverse event reporting system[J]. Contraception, 2021, 103(4): 222-224.
31.	Privitera M, Richy FF, Schabert VF. Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures[J]. Epilepsy Behav, 2022, 126: 108429.
32.	Lattanzi S, Trinka E, Zaccara G, et al. Third-generation antiseizure medications for adjunctive treatment of focal-onset seizures in adults: a systematic review and network meta-analysis[J]. Drugs, 2022, 82(2): 199-218.
33.	Cutillo G, Tolba H, Hirsch LJ. Anti-seizure medications and efficacy against focal to bilateral tonic-clonic seizures: a systematic review with relevance for SUDEP prevention[J]. Epilepsy Behav, 2021, 117: 107815.
34.	Pe?a-Ceballos J, Moloney PB, Munteanu T, et al. Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: a "real-world" retrospective study[J]. Epilepsia, 2023, 64(5): 1225-1235.
35.	Rosenfeld WE, Ferrari L, Kamin M. Efficacy of cenobamate by focal seizure subtypes: Post-hoc analysis of a phase 3, multicenter, open-label study[J]. Epilepsy Res, 2022, 183: 106940.
36.	Makridis KL, Friedo AL, Kellinghaus C, et al. Successful treatment of adult Dravet syndrome patients with cenobamate[J]. Epilepsia, 2022, 63(12): e164-e171.
37.	Keough K, Romick A. Cenobamate for adjunctive treatment in adult and pediatric patients with refractory Lennox-Gastaut syndrome: a retrospective chart review[J]. Neurol Ther, 2025, 14(4): 1685-1694.
38.	Falcicchio G, Lattanzi S, Negri F, et al. Treatment with cenobamate in adult patients with Lennox-Gastaut syndrome: a case series[J]. J Clin Med, 2022, 12(1): 125.
39.	Cagigal R, Romero-del-Rincon C, Fernandez-Perrone A, et al. Lack of effectiveness and seizure worsening with cenobamate in pediatric patients with Dravet syndrome[J]. Epilepsia, 2025, 66(6): e83-e89.

1. Ding D, Zhou D, Sander JW, et al. Epilepsy in China: major progress in the past two decades[J]. Lancet Neurol, 2021, 20(4): 316-326.
2. Ioannou P, Foster DL, Sander J W, et al. The burden of epilepsy and unmet need in people with focal seizures[J]. Brain Behav, 2022, 12(9): e2589.
3. Ben-Menachem E, Schmitz B, K?lvi?inen R, et al. The burden of chronic drug-refractory focal onset epilepsy: Can it be prevented[J]? Epilepsy Behav, 2023, 148: 109435.
4. Rosenfeld WE. Epilepsy medication management: Addressing common treatment barriers to adopting cenobamate and other new antiseizure medications[J]. Epilepsia, 2025, 66(Suppl 1): 38-48.
5. Sankar R, Ferrari L, Kamin M. Exploration of the mechanism of action of cenobamate[J]. Seizure, 2026, 134: 79-85.
6. Brigo F, Lattanzi S. Cenobamate add-on therapy for drug-resistant focal epilepsy[J]. Cochrane Database Syst Rev, 2024, 8(8): Cd014941.
7. Kamaraj AK, Szuromi MP. Modelling dysfunction-specific interventions for seizure termination in epilepsy[J]. NPJ Syst Biol Appl, 2025, 12(1): 9.
8. Yan R, Zhang H, Hong Z, et al. Sodium channel blockers for the treatment of focal epilepsy: A Chinese expert consensus[J]. Seizure, 2025, 127: 105-114.
9. Nakamura M, Cho JH, Shin H, et al. Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons[J]. Eur J Pharmacol, 2019, 855: 175-182.
10. Müller P, Draguhn A, Egorov AV. Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers[J]. Pflugers Arch, 2024, 476(10): 1445-1473.
11. Sharma R, Nakamura M, Neupane C, et al. Positive allosteric modulation of GABA(A) receptors by a novel antiepileptic drug cenobamate[J]. Eur J Pharmacol, 2020, 879: 173117.
12. Kim JJ, Gharpure A, Teng J, et al. Shared structural mechanisms of general anaesthetics and benzodiazepines[J]. Nature, 2020, 585(7824): 303-308.
13. Steinhoff BJ, Georgiou D, Dietmann D, et al. Cenobamate plasma levels in patients with epilepsy: correlation with efficacy and tolerability[J]? J Clin Med, 2024, 13(10): e10256.
14. Yang E, Sunwoo J, Huh KY, et al. Pharmacokinetics and safety of cenobamate, a novel antiseizure medication, in healthy Japanese, and an ethnic comparison with healthy non-Japanese[J]. Clin Transl Sci, 2022, 15(2): 490-500.
15. Rissardo J , Fornari Caprara AL. Cenobamate (YKP3089) and drug-resistant epilepsy: a review of the literature[J]. Medicina (Kaunas), 2023, 59(8): 12-16.
16. 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[J]. Lancet Neurol, 2020, 19(1): 38-48.
17. Lee SK, Yu P, Choe E, et al. A randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of adjunctive cenobamate in Asian patients with focal seizures[J]. Epilepsia, 2026, 67(2): 660-672.
18. Yu P, Wu X, Cui L, et al. Efficacy and safety of adjunctive cenobamate in chinese participants with focal seizure[J]. Adv Ther, 2026, 43(2): 688-709.
19. Klein P, Aboumatar S, Brandt C, et al. Long-term efficacy and safety from an open-label extension of adjunctive Cenobamate in patients with uncontrolled focal seizures[J]. Neurology, 2022, 99(10): e989-e998.
20. Makridis KL, Kaindl AM. Real-world experience with cenobamate: a systematic review and meta-analysis[J]. Seizure, 2023, 112: 1-10.
21. Bosak M, Podraza H, W?och-Kope? D, et al. Efficacy and safety of Cenobamate: a multicenter, retrospective evaluation of real-world clinical practice[J]. Seizure, 2025, 130: 25-31.
22. Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures[J]. Neurology, 2020, 94(22): e2311-e2322.
23. Sperling M R, 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[J]. Epilepsia, 2020, 61(6): 1099-1108.
24. 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[J]. Epilepsy Behav, 2021, 123: 108270.
25. Ferrari L, Rosenfeld WE, Kamin M. A global update on cenobamate based on real-world experience in over 100 000 patients[J]. Epilepsia, 2024, 65(4): 1149-1150.
26. Darpó B, Sager PT, Xue H, et al. A Phase 1 Clinical study evaluating the effects of cenobamate on the QT interval[J]. Clin Pharmacol Drug Dev, 2022, 11(4): 523-534.
27. Giannelli T, Falcicchio G. Drug-induced liver injury during valproic acid and cenobamate coadministration: a direct consequence or an unforeseen event[J]? Neurol Sci, 2025, 46(3): 1419-1420.
28. Greene SA, Kwak C, Kamin M, et al. Effect of cenobamate on the single-dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects[J]. Clin Transl Sci, 2022, 15(4): 899-911.
29. Smith MC, Klein P, Krauss GL, et al. Dose adjustment of concomitant antiseizure medications during Cenobamate treatment: expert opinion consensus recommendations[J]. Neurol Ther, 2022, 11(4): 1705-1720.
30. Sunaga T, Cicali B, Schmidt S, et al. Comparison of contraceptive failures associated with CYP3A4-inducing drug-drug interactions by route of hormonal contraceptive in an adverse event reporting system[J]. Contraception, 2021, 103(4): 222-224.
31. Privitera M, Richy FF, Schabert VF. Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures[J]. Epilepsy Behav, 2022, 126: 108429.
32. Lattanzi S, Trinka E, Zaccara G, et al. Third-generation antiseizure medications for adjunctive treatment of focal-onset seizures in adults: a systematic review and network meta-analysis[J]. Drugs, 2022, 82(2): 199-218.
33. Cutillo G, Tolba H, Hirsch LJ. Anti-seizure medications and efficacy against focal to bilateral tonic-clonic seizures: a systematic review with relevance for SUDEP prevention[J]. Epilepsy Behav, 2021, 117: 107815.
34. Pe?a-Ceballos J, Moloney PB, Munteanu T, et al. Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: a "real-world" retrospective study[J]. Epilepsia, 2023, 64(5): 1225-1235.
35. Rosenfeld WE, Ferrari L, Kamin M. Efficacy of cenobamate by focal seizure subtypes: Post-hoc analysis of a phase 3, multicenter, open-label study[J]. Epilepsy Res, 2022, 183: 106940.
36. Makridis KL, Friedo AL, Kellinghaus C, et al. Successful treatment of adult Dravet syndrome patients with cenobamate[J]. Epilepsia, 2022, 63(12): e164-e171.
37. Keough K, Romick A. Cenobamate for adjunctive treatment in adult and pediatric patients with refractory Lennox-Gastaut syndrome: a retrospective chart review[J]. Neurol Ther, 2025, 14(4): 1685-1694.
38. Falcicchio G, Lattanzi S, Negri F, et al. Treatment with cenobamate in adult patients with Lennox-Gastaut syndrome: a case series[J]. J Clin Med, 2022, 12(1): 125.
39. Cagigal R, Romero-del-Rincon C, Fernandez-Perrone A, et al. Lack of effectiveness and seizure worsening with cenobamate in pediatric patients with Dravet syndrome[J]. Epilepsia, 2025, 66(6): e83-e89.

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Pharmacological mechanisms and clinical research progress of cenobamate

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