Chapter 33
Eslicarbazepine Acetate
Meir Bialer,
Christian Elger,
Meir Bialer
The Hebrew University of Jerusalem and David R. Bloom Center for Pharmacy, Jerusalem, Israel
Search for more papers by this authorMeir Bialer,
Christian Elger,
Meir Bialer
The Hebrew University of Jerusalem and David R. Bloom Center for Pharmacy, Jerusalem, Israel
Search for more papers by this authorBook Editor(s):Simon Shorvon MA MB BChir MD FRCP,
Emilio Perucca MD PhD FRCP(Edin),
Jerome Engel Jr. MD PhD,
Simon Shorvon MA MB BChir MD FRCP
Professor in Clinical Neurology and Consultant Neurologist
UCL Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, London, UK
Search for more papers by this authorEmilio Perucca MD PhD FRCP(Edin)
Professor of Medical Pharmacology and Director, Clinical Trial Center
Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics University of Pavia, C. Mondino National Neurological Institute Pavia, Italy
Search for more papers by this authorJerome Engel Jr. MD PhD
Jonathan Sinay Distinguished Professor of Neurology and Director UCLA Seizure Disorder Center
Neurobiology, and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, USA
Search for more papers by this authorFirst published: 02 October 2015
Summary
Eslicarbazepine acetate (ESL) is a voltage-gated sodium and calcium channel blocker that was identified as a promising candidate for clinical development in epilepsy through a drug discovery programme initiated in the mid-1990s by BIAL. This chapter reviews the preclinical pharmacology and the clinical pharmacokinetics, efficacy and safety data of ESL in epilepsy. Studies in other indications (neuropathic pain, bipolar disorder, fibromyalgia and migraine prophylaxis) show limited efficacy and are not addressed here. Plasma and urine concentrations of ESL and its metabolites can be monitored by solid phase extraction followed by high performance liquid chromatography (HPLC), with ultraviolet or mass spectrometric detection. Routine monitoring of serum eslicarbazepine levels is not recommended, and a reference serum eslicarbazepine concentrations in patients receiving ESL therapy has not yet been clearly established. About 30% of patients with epilepsy are uncontrolled with available treatments and a further 25% develop manifestations of drug toxicity.
References
- Benés J, Soares-da-Silva P. Substituted dihydrodibenzo/B,F/azepine, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compositions containing them. USPTO patent no. 5753646, 19 May 1998.
- Bialer M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs 2006; 15: 637–647.
- Benes J, Parada A, Figueiredo AA, et al. Anticonvulsant and sodium channel-blocking properties of novel 10,11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem 1999; 42: 2582–2587.
- Hainzl D, Parada A, Soares-da-Silva P. Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(-)-10,11-dihydro-10-hydroxy carbamazepine. Epilepsy Res 2001; 44: 197–206.
- Volosov A, Xiaodong S, Perucca E, et al. Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects. Clin Pharmacol Ther 1999; 66: 547–553.
- Soares-da-Silva P, Pires N, Bonifácio MJ, et al. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. Pharmacol Res Perspect 2015; 3: e00124.
- Bonifacio MJ, Sheridan RD, Parada A, et al. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia 2001; 42: 600–608.
- Almeida L, Soares-da-Silva P. Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics 2007; 4: 88–96.
- Hebeisen S, Soares-da-Silva P. Slow and fast inactivation of voltage-gated sodium channels by eslicarbazepine, carbamazepine, oxcarbazepine and lacosamide. Epilepsy Curr 2012; 13(Suppl 1): 414–415.
- Hebeisen S, Pires N, Loureiro AI, 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.
- Brady K, Hebeisen S, Konrad D, Soares-da-Silva P. The effects of eslicarbazepine, R-licarbazepine, oxcarbazepine and carbamazepine on ion transmission Cav3.2 channels. Epilepsia 2011; 52(Suppl 6): 260.
- Bonifacio MJ, Bulling A, Hebeisen S, et al. Eslicarbazepine and R-licarbazepine do not have effects on ion transmission through alpha1, alpha2, alpha3 and alpha5 GABA channels. Epilepsia 2011; 52(Suppl 6): 258.
- Soares-da-Silva P, Bulling A, Hebeisen S, Konrad D. The effects of eslicarbazepine, R-licarbazepine and carbamazepine on ion transmission through Kv7.2 channels. Epilepsia 2011; 52(Suppl 6): 258–259.
- Pires N, Palma N, Loureiro AI, et al. Effects of eslicarbazepine acetate, eslicarbazepine, carbamazepine and oxcarbazepine in the maximal electroconvulsive test in the mice. Epilepsia 2011; 52(Suppl 6): 118.
- Torrao L, Machado R, Pires N, et al. The effects of eslicarbazepine acetate, eslicarbazepine, carbamazepine and oxcarbazepine in the 6-Hz psychomotor seizure model in the mice. Epilepsia 2011; 52(Suppl 6): 118–119.
- Potschka H, Soerensen J, Pekcec A, et al. Effect of eslicarbazepine acetate in the corneal kindling progression and the amygdala kindling model of temporal lobe epilepsy. Epilepsy Res 2014; 108: 212–222.
- Pekcec A, Potschka H, Soares-da-Silva P. Effects of eslicarbazepine acetate and its metabolites in the corneal kindling model of epilepsy. Epilepsia 2011; 52(Suppl 6): 257.
- Sierra-Paredes G, Loureiro AI, Wright LC, et al. Effects of eslicarbazepine acetate on acute and chronic latrunculin A-induced seizures and extracellular amino acid levels in the mouse hippocampus. Epilepsia 2013; 54(Suppl 3): 153.
- Pires N, Bonifacio MJ, Wright LC, et al. (eds). Eslicarbazepine acetate is antiepileptogenic in the pilocarpine mouse model of temporal lobe epilepsy. 67th Annual Meeting of the American Epilepsy Society; 2013; Washington, DC.
- Almeida L, Potgieter JH, Maia J, et al. Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment. Eur J Clin Pharmacol 2008; 64: 267–273.
- Almeida L, Soares-da-Silva P. Safety, tolerability and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic agent, during first administration to humans. Drugs R D 2003; 4: 269–284.
- Almeida L, Soares-da-Silva P. Safety, tolerability, and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans. J Clin Pharmacol 2004; 44: 906–918.
- Bialer M, Soares-da-Silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia 2012; 53: 935–946.
- Maia J, Vaz-da-Silva M, Almeida L, et al. Effect of food on the pharmacokinetic profile of eslicarbazepine acetate (BIA 2-093). Drugs R D 2005; 6: 201–206.
- Vaz-da-Silva M, Nunes T, Soares E, et al. Eslicarbazepine acetate pharmacokinetics after single and repeated doses in healthy subjects. Epilepsia 2005; 46(Suppl 8): 191.
- Falcao A, Maia J, Almeida L, et al. Effect of gender on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel blocker. Biopharm Drug Dispos 2007; 28: 249–256.
- Maia J, Almeida L, Falcão A, et al. Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther 2008; 46: 119–130.
- Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J Clin Pharmacol 1995; 35: 763–766.
- Nunes T, Rocha JF, Falcao A, et al. Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. Epilepsia 2013; 54: 108–116.
- Perucca E, Elger C, Halasz P, et al. Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures. Epilepsy Res 2011; 96: 132–139.
- Almeida L, Minciu I, Nunes T, et al. Pharmacokinetics, efficacy and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol 2008; 48: 966–977.
- Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII). Epilepsy Res 2007; 73: 1–52.
- Almeida L, Nunes T, Sicard E, et al. Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects. Acta Neurol Scand 2010; 121: 257–264.
- Nunes T, Sicard E, Almeida L, et al.. Pharmacokinetic interaction study between eslicarbazepine acetate and topiramate in healthy subjects. Curr Med Res Opin 2010; 26: 1355–1362.
- Vaz-da-Silva M, Almeida L, Falcao A, et al. Effect of eslicarbazepine acetate on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects during a three-stage, open-label, multiple-dose, single-period study. Clin Ther 2010; 32: 179–192.
- Vaz da Silva M, Costa R, Soares E, et al. Effect of eslicarbazepine acetate on the pharmacokinetics of digoxin in healthy subjects. Fund Clin Pharmacol 2009; 23: 509–514.
- Falcao A, Vaz-da-Silva M, Gama H, et al. Effect of eslicarbazepine acetate on the pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive in healthy women. Epilepsy Res 2013; 105: 368–376.
- Falcao A, Pinto R, Nunes T, Soares-da-Silva P. Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects. Epilepsy Res 2013; 106: 244–249.
- 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 8 May 2015).
- European Medicines Agency. Zebinix (eslicarbazepine acetate): EU summary of product characteristics. Available from: www.ema.europa.eu (accessed 8 May 2015).
- Almeida L, Falcao A, Maia J, et al. Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy elderly and young subjects. J Clin Pharmacol 2005; 45: 1062–1066.
- Fontes-Ribeiro C, Nunes T, Falcão A, et al. Eslicarbazepine acetate (BIA 2-093): relative bioavailability and bioequivalence of 50 mg/mL oral suspension and 200 mg and 800 mg tablet formulations. Drugs R D 2005; 6: 253–260.
- Elger C, Bialer M, Falcao A, et al. Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers. Epilepsia 2013; 54: 1453–1461.
- Falcao A, Fuseau E, Nunes T, et al. Pharmacokinetics, drug interactions and exposure–response relationship of eslicarbazepine acetate in adult patients with partial-onset seizures: population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses. CNS Drugs 2012; 26: 79–91.
- Elger C, Bialer M, Cramer JA, et al. Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia 2007; 48: 497–504.
- Sperling M, Harvey J, Biraben A, et al. (eds). Adjunctive eslicarbazepine acetate in patients with refractory partial-onset seizures: efficacy results of a 12 week randomized placebo-controlled study. 67th Annual Meeting of the American Epilepsy Society; 2013; Washington, DC.
- 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: 98–107.
- Abou-Khalil B, Rogin JB, Biraben A, et al. (eds). Eslicarbazepine acetate as adjunctive therapy in patients with refractory partial-onset seizures: safety results of a 12 week randomized placebo-controlled study. 67th Annual Meeting of the American Epilepsy Society; 2013; Washington, DC.
- Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res 2010; 89: 278–285.
- Gil-Nagel A, Lopes-Lima J, Almeida L, et al. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand 2009; 120: 281–287.
- Elger C, Halasz P, Maia J, Almeida L, Soares-da-Silva P. 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: 454–463.
- MR Sperling, J Harvey, D Blum, T Grinnell (eds). Conversion to monotherapy with eslicarbazepine acetate in adults with partial-onset seizures: results of a North American study. 67th Annual Meeting of the American Epilepsy Society; 2013; Washington, DC.
- Pazdera L, Jacobson MP, Bhatia P, et al, editors. Conversion to monotherapy with eslicarbazepine acetate in adults with partial-onset seizures. 67th Annual Meeting of the American Epilepsy Society; 2013; Washington, DC.
- French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia 2010; 51: 1936–1943.
- Halasz P, Cramer JA, Hodoba D, 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: 1963–1969.
- 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 Res 2013; 103: 262–269.
- Lopes-Lima J, Gil-Nagel A, Maia J, et al. AES Proceedings. Long-term treatment of partial epilepsy with eslicarbazepine acetate (ESL): results of a one-year open-label extension of study BIA-2093-303. Epilepsia 2008; 49(Suppl 7): 441–442.
- Vaz-da-Silva M, Nunes T, Almeida L, et al. Evaluation of eslicarbazepine acetate on cardiac repolarization in a thorough QT/QTc study. J Clin Pharmacol 2012; 52: 222–233.
- Steinhoff BJ, Trinka E, Wendling AS. Abrupt switch from extended-release oxcarbazepine to eslicarbazepine acetate. [in German] Nervenarzt 2011; 82: 764–767.
