In a manuscript just published in “BRAIN”, a journal of neurology, Anna Doeser et al (1) provide evidence on how eslicarbazepine, the main active metabolite of eslicarbazepine acetate, overcomes a cellular resistance mechanism to conventional antiepileptic drugs. Furthermore, eslicarbazepine acetate showed an antiepileptogenic effect in an animal model of chronic epilepsy, likely associated with the eslicarbazepine-induced inhibition of Cav3.2 T-type Ca2+ channels, which have been shown to be key mediators of epileptogenesis (1).
Eslicarbazepine acetate, a once-daily antiepileptic drug, is currently approved in the European Union (Zebinix®), United States and Canada (Aptiom®), for the adjunctive treatment of partial-onset seizures in adults (2,3).
Chronically epileptic tissue was obtained from epileptic patients that underwent brain surgery in an attempt to control their seizures and from rats with previously induced chronic epilepsy. Electrophysiological studies performed in hippocampal cells derived from those tissues showed that eslicarbazepine maintained its activity on sodium channels, with significant additional effects to carbamazepine (a classic antiepileptic drug) (1).
The antiepileptogenic effects were tested in a standard animal model of chronic epilepsy. Eslicarbazepine acetate was transiently administered (p.o., once-daily for 6 weeks) starting nine days after induction of epilepsy in mice through the injection of pilocarpine. Control mice were administered placebo instead of eslicarbazepine acetate, during the same 6-week period. Importantly, eight weeks after the end of treatment, mice that had received eslicarbazepine acetate showed significantly less spontaneous seizures and a pronounced reduction in neuropathology. Thus, eslicarbazepine acetate proved to be the first drug approved for use in humans that results in pronounced antiepileptogenic effects (1).
These findings are of critical importance because two major limitations of currently available treatments for epilepsy are that i) around one third of patients are uncontrolled despite being treated with anticonvulsant drugs and ii) currently available treatments so far act mainly by inhibiting seizure activity, but do not target the underlying disease process (4,5). “This publication offers an explanation as to why some of the patients with resistance to carbamazepine responded to eslicarbazepine acetate in the previous phase III trials. Also of note, the authors have presented evidence that suggests eslicarbazepine acetate may have anti-epileptogenic effects, which needs of course to be confirmed in properly conducted studies in humans” commented Holger Lerche, University of Tu?bingen, Department of Neurology and Epileptology, Hertie-Institute of Clinical Brain Research, Germany.
1. Doeser A, Dickhof G, et al. Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug. Brain. 2014. First published online: 3 December 2014.
2. European Medicines Agency. Zebinix (eslicarbazepine acetate): EU summary of product characteristics. Available from: http://www.ema.europa.eu (accessed 27 September 2014)
3. Sunovion Pharmaceuticals Inc. Aptiom® (eslicarbazepine acetate) tablets, for oral use: US prescribing information. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022416s000lbl.pdf. (accessed 27 September 2014).
4. Brodie MJ, Barry SJ, Bamagous GA et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;15;78(20):1548-54.
5. Trinka E, Brigo F. Antiepileptogenesis in humans: disappointing clinical evidence and ways to move forward. Current Opinion in Neurology. 2014;27:227–235
6. Bialer M, Soares-da-Silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia 2012;53(6):935-46.
7. Hebeisen S, Pires N et al. Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: A comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology. 2015;89:122- 135.
8. Brady K, Hebeisen S et al. The effects of eslicarbazepine, R-licarbazepine, oxcarbazepine and carbamazepine on ion transmission Cav3.2 channels. Epilepsia 2011;52(Suppl.6):260.
9. Elger C, Bialer M, Cramer J et al. Eslicarbazepine acetate: a double-blind, add-on placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia. 2007;48(3):497-504.
10. Elger C, Hala?sz P, Maia J et al. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia. 2009;50(3):454-463.
11. Ben-Menachem E, Gabbai A, Hufnagel A et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Research. 2010;89:278-285.
12. Lopes-Lima J, Gil-Nagel A, Maia J et al. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurologica Scandinavica. 2009;120:281-287.
13. Sperling M, Harvey J, Biraben A et al. Adjunctive eslicarbazepine acetate in patients with refractory partial-onset seizures: efficacy results of a 12 week randomized placebo-controlled study. Epilepsy Currents. 2014;14(Suppl 1):P3.210.
14. Abou-Khalil B, Rogin J, Biraben A et al. Eslicarbazepine acetate as adjunctive therapy in patients with refractory partial-onset seizures: safety results of a 12-week randomized placebo-controlled study. Epilepsy Currents. 2014;14(Suppl 1):P2.128.
15. Gil-Nagel A, Elger C, Ben-Menachem E et al. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia. 2013;54(1):98-107
16. Hala?sz P, Elger C, Guekht A et al. Long-term efficacy and safety of eslicarbazepine acetate: Results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy. Epilepsia. 2010;51(10):1963-1969.
17. Hufnagel A, Ben-Menachem E, Gabbai AA et al. Long-term safety and efficacy of eslicarbazepine acetate as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy: results of a 1-year open- label extension study. Epilepsy Research. 2013;103(2-3):262-9.