Русский журнал детской неврологии. 2018; 13: 45-55
Эффективность и переносимость бриварацетама в лечении эпилепсии: обзор литературы и собственные данные
https://doi.org/10.17650/2073-8803-2018-13-3-45-56Аннотация
Введение. Несмотря на значительные успехи, достигнутые в эпилептологии, резистентные к терапии эпилепсии составляют примерно 30 % среди всех форм этого заболевания. Даже с учетом широких возможностей применения современных медикаментозных и немедикаментозных методов лечения остается значительная часть пациентов с устойчивой к лечению эпилепсией, у которых оперативное лечение невозможно и альтернативные методы (стимуляция блуждающего нерва и кетогенная диета) неэффективны. В этой группе пациентов сохраняет свою актуальность фармакотерапия с поиском новых эффективных антиэпилептических препаратов (АЭП). В статье приведены данные литературы и результаты собственных исследований эффективности и переносимости нового АЭП бриварацетама (бривиак) у пациентов с труднокурабельной фокальной эпилепсией.
Материалы и методы. В исследование включено 8 пациентов в возрасте от 16 до 35 лет (средний возраст – 18,3 года; из них 2 пациента мужского пола, 6 – женского) с труднокурабельной фокальной эпилепсией, наблюдавшихся в ИДНЭ им. Свт. Луки и ИДВНЭ им Свт. Луки в период с 1 февраля 2017 г. по 1 сентября 2018 г. и получавших бриварацетам в качестве дополнительного препарата для лечения фокальных и билатеральных судорожных приступов. Период катамнестического наблюдения составил от 1 до 7,5 мес. Бриварацетам был добавлен к 1–2 АЭП (вальпроат, топирамат, карбамазепин/окскарбазепин) в дозе от 100 до 200 мг/сут в 2 приема.
Результаты и обсуждение. Эффективность >50 % (снижение частоты приступов на 50 % и более) была зарегистрирована у 4 (50 %) пациентов, снижение частоты приступов на 25–50 % – у 2 (25 %) пациентов. Минимальная клиническая эффективность и отсутствие эффекта отмечены в 1 (12,5 %) случае, аггравация приступов (фокальных моторных) зарегистрирована в 1 (12,5 %) случае. Бриварацетам существенно уменьшил тяжесть (выраженность и продолжительность) эпилептических приступов у 70 % больных. У 4 пациентов отмечено существенное улучшение на электроэнцефалограмме в виде уменьшения индекса эпилептиформной активности, у 1 пациента – полное блокирование эпилептиформной активности. Наибольшая эффективность бриварацетама отмечена в отношении билатеральных судорожных приступов: они отсутствуют на фоне терапии у 4 из 5 больных с приступами этого типа.
В нашем исследовании отмечена хорошая переносимость бриварацетама; побочных эффектов не зарегистрировано. В настоящее время 6 (75 %) из 8 пациентов продолжают терапию бриварацетамом. Важно отметить, что ни в одном случае бриварацетам не был отменен в связи с плохой переносимостью. Следует учитывать, что во всех случаях бриварацетам был назначен пациентам, абсолютно резистентным ко многим (более 2–3) АЭП.
Заключение. Результаты нашего исследования показывают высокую эффективность и хорошую переносимость бриварацетама у пациентов с фокальной эпилепсией и согласуются с данными, представленными в зарубежных публикациях.
Список литературы
1. Карлов В.А., Власов П.Н., Жидкова И.А. и др. Бриварацетам в лечении больных эпилепсией. Журнал неврологии и психиатрии им. С.С. Корсакова 2017;117(9):55–62.
2. Инструкция по применению препарата Бривиак®. Доступно по: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=b8cf75da-e645-4d3daa29-a64a9e35cd6f&t. .
3. Andres E., Kerling F., Hamer H., Winterholler M. Behavioural changes in patients with intellectual disability treated with brivaracetam. Acta Neurol Scand 2018;138(3):195–202. PMID: 29658982. DOI: 10.1111/ane.12943.
4. Ben-Menachem E., Mameniškienė R., Quarato P.P. et al. Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies. Neurology 2016;87(3):314–23. PMID: 27335114. DOI: 10.1212/WNL.0000000000002864.
5. Biton V., Berkovic S.F., Abou-Khalil B. et al. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia 2014;55(1):57–66. PMID: 24446953. DOI: 10.1111/epi.12433.
6. Brodie M.J., Fakhoury T., McDonough B. et al. Brivaracetam-induced elevation of carbamazepine epoxide levels: A posthoc analysis from the clinical development program. Epilepsy Res 2018;145:55–62. DOI: 10.1016/j.eplepsyres.2018.06.002.
7. Diaz A., Elmoufti S., Schiemann J., Whitesides J. Efficacy and safety of adjunctive brivaracetam for partial-onset (focal) seizures (POS) in patients with Type IC seizures at baseline: Pooled results from three fixed-dose, randomized, doubleblind, placebo-controlled, phase III studies. Neurology 2016;86(16 Suppl). Annual meeting of the 68th American Academy of Neurology (AAN), April 15–21, 2016, Vancouver, Canada. Abstr. P2.042.
8. French J.A., Costantini C., Brodsky A. et al. Adjunctive Brivaracetam for refractory partial-onset seizures: a randomized, controlled trial. Neurology 2010;75(6):519–25. DOI: 10.1212/WNL.0b013e3181ec7f7f.
9. Hirsch M., Hintz M., Specht A., SchulzeBonhage A. Tolerability, efficacy and retention rate of Brivaracetam in patients previously treated with Levetiracetam: a monocenter retrospective outcome analysis. Seizure 2018;61:98–103. PMID: 30118932. DOI: 10.1016/j.seizure.2018.07.017.
10. Klein P., Schiemann J., Sperling M.R. et al. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive Brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia 2015;56(12):1890–8. PMID: 26471380. DOI: 10.1111/epi.13212.
11. Klein P., Diaz A., Gasalla T., Whitesides J. A review of the pharmacology and clinical efficacy of brivaracetam. Clin Pharmacol 2018;10:1–22. PMID: 29403319. DOI: 10.2147/CPAA.S114072.
12. Kwan P., Trinka E., van Paesschen W. et al. Adjunctive Brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia 2014;55(1):38–46. PMID: 24116853. DOI: 10.1111/epi.12391.
13. Kwan P., Brodie M.J. Epilepsy after the first drug fails: substitution or add-on? Seizure 2000;9(7):464–8. PMID: 11034869. DOI: 10.1053/seiz.2000.0442.
14. Kwan P., Brodie M.J. Refractory epilepsy: mechanisms and solutions. Expert Rev Neurother 2006;6(3):397–406. PMID: 16533143. DOI: 10.1586/14737175.6.3.397.
15. Ryvlin P., Werhahn K.J., Blaszczyk B. et al. Adjunctive Brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia 2014;55(1):47–56. PMID: 24256083. DOI: 10.1111/epi.12432.
16. Sanon N.T., Gagné J., Wolf D.C. et al. Favorable adverse effect profile of brivaracetam vs levetiracetam in a preclinical model. Epilepsy Behav 2018;79:117–25. PMID: 29287214. DOI: 10.1016/j.yebeh.2017.11.019.
17. Shoenmarker N., Wade J.R., Stockis A. Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years. Eur J Clin Pharmacol 2017;73(6):727–33. PMID: 28280887. DOI: 10.1007/s00228-017-2230-6.
18. Stephen L.J., Brodie M.J. Brivaracetam: a novel antiepileptic drug for focal-onset seizures. Ther Adv Neurol Disord 2017;11:1756285617742081. PMID: 29399049. DOI: 10.1177/1756285617742081.
19. Strzelczyk A., Steinig I., Klein K.M. et al. Brivaracetam for add-on treatment in focal epilepsy. Nervenarzt 2016;87(10):1086–93. PMID: 27389600. DOI: 10.1007/s00115016-0163-4.
20. Strzelczyk A., Kay L., Bauer S. et al. Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus. Epilepsia 2018;59(8):1549–56. PMID: 29943451. DOI: 10.1111/epi.14476.
21. Strzelczyk A., Klein K.M., Willems L.M. et al. Brivaracetam in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus. Expert Rev Clin Pharmacol 2016;9(5):637–45. PMID: 26891946. DOI: 10.1586/17512433.2016.1156529.
22. Toledo M., Whitesides J., Schiemann J. et al. Safety, tolerability, and seizure control during long-term treatment with adjunctive Brivaracetam for partial-onset seizures. Epilepsia 2016;57(7):1139–51. PMID: 27265725. DOI: 10.1111/epi.13416.
23. Van Paesschen W., Hirsch E., Johnson M. et al. Efficacy and tolerability of adjunctive Brivaracetam in adults with uncontrolled partial-onset seizures: a phase IIb, randomized, controlled trial. Epilepsia 2013;54(1):89–97. PMID: 22813235. DOI: 10.1111/j.1528-1167.2012.03598.x.
24. Willems L.M., Bertsche A., Bösebeck F. et al. Retention, and tolerability of brivaracetam in patients with epileptic encephalopathies: a multicenter cohort study from Germany. Front Neurol 201823;9:569. PMID: 30083127. DOI: 10.3389/fneur.2018.00569.
25. Wood M.D., Sands Z.A., Vandenplas C., Gillard M. Further evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia 2018;59(9):e147–51. PMID: 30144048. DOI: 10.1111/epi.14532.
26. Xiao X., Ouyang Y., Song Z., Zheng W. Progress in synaptic mechanism in epileptogenesis. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018;43(1):90–4. PMID: 30154297. DOI: 10.11817/j.issn.1672-7347.2018.01.014.
27. Zahnert F., Krause K., Immisch I. et al. Brivaracetam in the treatment of patients with epilepsy-first clinical experiences. Front Neurol 2018;6;9:38. PMID: 29467714. DOI: 10.3389/fneur.2018.00038.
Russian Journal of Child Neurology. 2018; 13: 45-55
Efficacy and tolerability of brivaracetam in the treatment of epilepsy: literature review and own experience
https://doi.org/10.17650/2073-8803-2018-13-3-45-56Abstract
Background. Despite significant advances in epileptology, approximately 30 % of patients suffer from drug-resistant epilepsy. Numerous approaches are currently available to treat epilepsy; however, there are still many patients with treatment-resistant disease, in whom surgery is impossible and alternative methods (vagus nerve stimulation and ketogenic diet) are ineffective. Thus, searching for new effective antiepileptic drugs (AED) for these patients remains highly relevant. In this article, we reviewed available publications and provided own results on the efficacy and tolerability of brivaracetam (Briviact®) in patients with intractable focal epilepsy.
Materials and methods. The study included 8 patients aged between 16 and 35 years (mean age 18.3 years; 2 males and 6 females) with intractable focal epilepsy treated at the Svt. Luka’s Institute of Child Neurology and Epilepsy between February 1st, 2017 and September 1st, 2018.
All patients received brivaracetam as an additional AED for the treatment of focal and bilateral convulsive seizures. Patients were followed up for 1 to 7.5 months. Brivaracetam was added to 1 or 2 AED (valproate, topiramate, or carbamazepine/oxcarbazepine) at a dose of 100–200 mg/day divided into 2 doses.
Results and discussion. Good therapeutic effect (more than 50 % reduction in seizure frequency) was registered in 4 patients (50 %). Two patients (25 %) achieved a 25–50 % reduction in seizure frequency. Minimal clinical efficacy with no effect was observed in one patient (12.5 %). One patient (12.5 %) had aggravation of focal and motor seizures. Brivaracetam significantly reduced the severity (intensity and duration) of epileptic seizures in 70 % of patients. Four patients demonstrated substantial improvements on electroencephalogram (decreased epileptiform activity). One patient had complete suppression of epileptiform activity. Brivaracetam was most effective for bilateral convulsive seizures: 4 out of 5 patients experienced complete relief of these seizures.
Brivaracetam demonstrated good tolerability: no side effects were registered in this study. Six out of 8 participants (75 %) currently continue treatment with brivaracetam. It is important that none of the patients had to stop brivaracetam due to poor tolerability. Of note, all of study participants started to receive brivaracetam because they had seizures resistant to multiple (more than 2–3) AED.
Conclusion. Our findings suggest high efficacy and good tolerability of brivaracetam in patients with focal epilepsy. Our results are also consistent with the data reported by foreign authors.
References
1. Karlov V.A., Vlasov P.N., Zhidkova I.A. i dr. Brivaratsetam v lechenii bol'nykh epilepsiei. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova 2017;117(9):55–62.
2. Instruktsiya po primeneniyu preparata Briviak®. Dostupno po: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=b8cf75da-e645-4d3daa29-a64a9e35cd6f&t. .
3. Andres E., Kerling F., Hamer H., Winterholler M. Behavioural changes in patients with intellectual disability treated with brivaracetam. Acta Neurol Scand 2018;138(3):195–202. PMID: 29658982. DOI: 10.1111/ane.12943.
4. Ben-Menachem E., Mameniškienė R., Quarato P.P. et al. Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies. Neurology 2016;87(3):314–23. PMID: 27335114. DOI: 10.1212/WNL.0000000000002864.
5. Biton V., Berkovic S.F., Abou-Khalil B. et al. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia 2014;55(1):57–66. PMID: 24446953. DOI: 10.1111/epi.12433.
6. Brodie M.J., Fakhoury T., McDonough B. et al. Brivaracetam-induced elevation of carbamazepine epoxide levels: A posthoc analysis from the clinical development program. Epilepsy Res 2018;145:55–62. DOI: 10.1016/j.eplepsyres.2018.06.002.
7. Diaz A., Elmoufti S., Schiemann J., Whitesides J. Efficacy and safety of adjunctive brivaracetam for partial-onset (focal) seizures (POS) in patients with Type IC seizures at baseline: Pooled results from three fixed-dose, randomized, doubleblind, placebo-controlled, phase III studies. Neurology 2016;86(16 Suppl). Annual meeting of the 68th American Academy of Neurology (AAN), April 15–21, 2016, Vancouver, Canada. Abstr. P2.042.
8. French J.A., Costantini C., Brodsky A. et al. Adjunctive Brivaracetam for refractory partial-onset seizures: a randomized, controlled trial. Neurology 2010;75(6):519–25. DOI: 10.1212/WNL.0b013e3181ec7f7f.
9. Hirsch M., Hintz M., Specht A., SchulzeBonhage A. Tolerability, efficacy and retention rate of Brivaracetam in patients previously treated with Levetiracetam: a monocenter retrospective outcome analysis. Seizure 2018;61:98–103. PMID: 30118932. DOI: 10.1016/j.seizure.2018.07.017.
10. Klein P., Schiemann J., Sperling M.R. et al. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive Brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia 2015;56(12):1890–8. PMID: 26471380. DOI: 10.1111/epi.13212.
11. Klein P., Diaz A., Gasalla T., Whitesides J. A review of the pharmacology and clinical efficacy of brivaracetam. Clin Pharmacol 2018;10:1–22. PMID: 29403319. DOI: 10.2147/CPAA.S114072.
12. Kwan P., Trinka E., van Paesschen W. et al. Adjunctive Brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia 2014;55(1):38–46. PMID: 24116853. DOI: 10.1111/epi.12391.
13. Kwan P., Brodie M.J. Epilepsy after the first drug fails: substitution or add-on? Seizure 2000;9(7):464–8. PMID: 11034869. DOI: 10.1053/seiz.2000.0442.
14. Kwan P., Brodie M.J. Refractory epilepsy: mechanisms and solutions. Expert Rev Neurother 2006;6(3):397–406. PMID: 16533143. DOI: 10.1586/14737175.6.3.397.
15. Ryvlin P., Werhahn K.J., Blaszczyk B. et al. Adjunctive Brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia 2014;55(1):47–56. PMID: 24256083. DOI: 10.1111/epi.12432.
16. Sanon N.T., Gagné J., Wolf D.C. et al. Favorable adverse effect profile of brivaracetam vs levetiracetam in a preclinical model. Epilepsy Behav 2018;79:117–25. PMID: 29287214. DOI: 10.1016/j.yebeh.2017.11.019.
17. Shoenmarker N., Wade J.R., Stockis A. Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years. Eur J Clin Pharmacol 2017;73(6):727–33. PMID: 28280887. DOI: 10.1007/s00228-017-2230-6.
18. Stephen L.J., Brodie M.J. Brivaracetam: a novel antiepileptic drug for focal-onset seizures. Ther Adv Neurol Disord 2017;11:1756285617742081. PMID: 29399049. DOI: 10.1177/1756285617742081.
19. Strzelczyk A., Steinig I., Klein K.M. et al. Brivaracetam for add-on treatment in focal epilepsy. Nervenarzt 2016;87(10):1086–93. PMID: 27389600. DOI: 10.1007/s00115016-0163-4.
20. Strzelczyk A., Kay L., Bauer S. et al. Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus. Epilepsia 2018;59(8):1549–56. PMID: 29943451. DOI: 10.1111/epi.14476.
21. Strzelczyk A., Klein K.M., Willems L.M. et al. Brivaracetam in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus. Expert Rev Clin Pharmacol 2016;9(5):637–45. PMID: 26891946. DOI: 10.1586/17512433.2016.1156529.
22. Toledo M., Whitesides J., Schiemann J. et al. Safety, tolerability, and seizure control during long-term treatment with adjunctive Brivaracetam for partial-onset seizures. Epilepsia 2016;57(7):1139–51. PMID: 27265725. DOI: 10.1111/epi.13416.
23. Van Paesschen W., Hirsch E., Johnson M. et al. Efficacy and tolerability of adjunctive Brivaracetam in adults with uncontrolled partial-onset seizures: a phase IIb, randomized, controlled trial. Epilepsia 2013;54(1):89–97. PMID: 22813235. DOI: 10.1111/j.1528-1167.2012.03598.x.
24. Willems L.M., Bertsche A., Bösebeck F. et al. Retention, and tolerability of brivaracetam in patients with epileptic encephalopathies: a multicenter cohort study from Germany. Front Neurol 201823;9:569. PMID: 30083127. DOI: 10.3389/fneur.2018.00569.
25. Wood M.D., Sands Z.A., Vandenplas C., Gillard M. Further evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia 2018;59(9):e147–51. PMID: 30144048. DOI: 10.1111/epi.14532.
26. Xiao X., Ouyang Y., Song Z., Zheng W. Progress in synaptic mechanism in epileptogenesis. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018;43(1):90–4. PMID: 30154297. DOI: 10.11817/j.issn.1672-7347.2018.01.014.
27. Zahnert F., Krause K., Immisch I. et al. Brivaracetam in the treatment of patients with epilepsy-first clinical experiences. Front Neurol 2018;6;9:38. PMID: 29467714. DOI: 10.3389/fneur.2018.00038.
