Skip to main content

A Review of the New Antiepileptic Drugs for Focal-Onset Seizures in Pediatrics: Role of Extrapolation

Abstract

Most antiepileptic drugs (AEDs) receive regulatory approval for children years after the drug is available in adults, encouraging off-label use of the drug in children and hindering attempts to obtain quality pediatric data in controlled trials. Extrapolating adult efficacy data to pediatrics can reduce the time between approval in adults and that in children. To extrapolate efficacy from adults to children, several assumptions must be supported, such as (1) a similar disease progression and response to interventions in adults and children, and (2) similar exposure response in adults and children. The Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE) addressed these assumptions in focal-onset seizures (FOS), the most common seizure type in both adults and children. PEACE reviewed the biological and clinical evidence that supported the assumptions that children with FOS have a similar disease progression and response to intervention as adults with FOS. After age 2 years, the pathophysiological underpinnings of FOS and the biological milieu in which seizures are initiated and propagated in children, seizure semiology, electroencephalographic features, etiology and AED response to FOS in children are similar to those in adults with FOS. PEACE concluded that extrapolation of efficacy data in adults to pediatrics in FOS is supported by strong scientific and clinical evidence. However, safety and pharmacokinetic (PK) data cannot be extrapolated from adults to children. Based on extrapolation, eslicarbazepine is now approved for children with FOS, down to age 4 years. Perampanel, lacosamide and brivaracetam are now undergoing PK and safety studies for the purposes of extrapolation down to age 2 or 4 years. When done in conjunction with PK and safety investigations in children, extrapolation of adult data from adults to children can reduce the time delay between approval of effective and safe AEDs in adults and approval in children.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Wirrell EC, Grossardt BR, Wong-Kisiel LC, Nickels KC. Incidence and classification of new-onset epilepsy and epilepsy syndromes in children in Olmsted County, Minnesota from 1980 to 2004: a population-based study. Epilepsy Res. 2011;95(1–2):110–8.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Forsgren L, Beghi E, Oun A, Sillanpaa M. The epidemiology of epilepsy in Europe—a systematic review. Eur J Neurol. 2005;12(4):245–53.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Hauser WA. Epidemiology of epilepsy in children. Neurosurg Clin N Am. 1995;6(3):419–29.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Franco V, Canevini MP, Capovilla G, De SG, Galimberti CA, Gatti G, et al. Off-label prescribing of antiepileptic drugs in pharmacoresistant epilepsy: a cross-sectional drug utilization study of tertiary care centers in Italy. CNS Drugs. 2014;28(10):939–49.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Palmaro A, Bissuel R, Renaud N, Durrieu G, Escourrou B, Oustric S, et al. Off-label prescribing in pediatric outpatients. Pediatrics. 2015;135(1):49–58.

    PubMed  Article  Google Scholar 

  6. 6.

    Bazzano AT, Mangione-Smith R, Schonlau M, Suttorp MJ, Brook RH. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9(2):81–8.

    PubMed  Article  Google Scholar 

  7. 7.

    Wheless JW. Safety of supratherapeutic doses of newer antiepileptic drugs in children: what have we really learned? J Pediatr Pharmacol Ther. 2017;22(4):244–5.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Amann JP, Glauser T, Chiron C. Developing antiepileptic drugs in children: balancing protection and access. Handb Clin Neurol. 2013;111:741–6.

    PubMed  Article  Google Scholar 

  9. 9.

    Messinger MM, Misra SN, Clark GD, DiCarlo SM. Evaluation of safety in exceeding maximum adult doses of commonly used second-generation antiepileptic drugs in pediatric patients. J Pediatr Pharmacol Ther. 2017;22(4):256–60.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Dunne J, Rodriguez WJ, Murphy MD, Beasley BN, Burckart GJ, Filie JD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242–9.

    PubMed  Article  Google Scholar 

  11. 11.

    Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs; revision of “Pediatric Use” subsection in the labeling; final rule. https://www.fda.gov/ohrms/dockets/ac/01/briefing/3778b1_Tab6_7-21CFR%20Part%20201.pdf. Accessed 18 Feb 2018.

  12. 12.

    EMA. European Medicines Agency. Concept paper on extrapolation of efficacy and safety in medicine development. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129285.pdf. Accessed 18 Feb 2018.

  13. 13.

    EMA. Reflection paper on extrapolation of efficacy and safety in paediatric medicine development—Draft. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/04/WC500204187.pdf. Accessed 18 Feb 2018.

  14. 14.

    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.ICH Harmonised Tripartite Guideline. E11. Clinical Investigation of medicinal Products in the Pediatric Population. 2000. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/guidelines/efficacy/E11/Step4/E11_Guideline.pdf. Accessed 18 Feb 2018.

  15. 15.

    International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Harmonised Guidline. Addendum to ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population. 2016. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/E11-R1EWG_Step4_Addendum_2017_0818.pdf. Accessed 18 Feb 2018.

  16. 16.

    Committee for Medicinal Products for Human Use (CHMP). Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population. EMEA/CHMP/EWP/147013/2004. 6-28-2006.

  17. 17.

    Cowan LD, Bodensteiner JB, Leviton A, Doherty L. Prevalence of the epilepsies in children and adolescents. Epilepsia. 1989;30(1):94–106.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Bulteau C, Jambaque I, Viguier D, Kieffer V, Dellatolas G, Dulac O. Epileptic syndromes, cognitive assessment and school placement: a study of 251 children. Dev Med Child Neurol. 2000;42(5):319–27.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Waaler PE, Blom BH, Skeidsvoll H, Mykletun A. Prevalence, classification, and severity of epilepsy in children in western Norway. Epilepsia. 2000;41(7):802–10.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Sillanpää M, Jalava M, Shinnar S. Epilepsy syndromes in patients with childhood-onset seizures in Finland. Pediatr Neurol. 1992;21:533–7.

    Article  Google Scholar 

  21. 21.

    Holmes GL and Noebels JL (eds). Epilepsy: the Biology of a Spectrum Disorder. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp 17–34.

  22. 22.

    Beydoun A. Monotherapy trials of new antiepileptic drugs. Epilepsia. 1997;38(Suppl 9):S21–31.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz O. Efficacy of antiepileptic drugs in adults predicts efficacy in children: a systematic review. Neurology. 2012;79(14):1482–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Pellock JM, Arzimanoglou A, D’Cruz O, Holmes GL, Nordli D, Shinnar S. Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥ 2 years of age with focal seizures: the case for disease similarity. Epilepsia. 2017;58(10):1686–96.

    PubMed  Article  Google Scholar 

  25. 25.

    Chiron C, Pons G. POS (partial onset seizures). Extrapolation from adults to children. Clin Setting. 2016. www.ema.europa.eu/docs/en_GB/document_library/Presentation/2016/05/WC500207579.pdf. Accessed 20 Feb 2018.

  26. 26.

    Wadsworth I, Jaki T, Sills GJ, Appleton R, Cross JH, Marson AG, et al. Clinical drug development in epilepsy revisited: a proposal for a new paradigm streamlined using extrapolation. CNS Drugs. 2016;30(11):1011–7.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Wadsworth I, Hampson LV, Jaki T. Extrapolation of efficacy and other data to support the development of new medicines for children: a systematic review of methods. Stat Methods Med Res. 2016.

  28. 28.

    Dichter M, Spencer WA. Penicillin-induced interictal discharges from the cat hippocampus. II. Mechanisms underlying origin and restriction. J Neurophysiol. 1969;32(5):663–87.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Kandel ER, Spencer WA. Excitation and inhibition of single pyramidal cells during hippocampal seizures. Exp Neurol. 1961;4:163–79.

    Article  Google Scholar 

  30. 30.

    Sawa M, Maruyama N, Kaji S. Intracellular potential recording during electrically induced seizures. Electroencephalogr Clin Neurophysiol. 1963;15:209–20.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Swann JW, Smith KL, Brady RJ. Localized excitatory synaptic interactions mediate the sustained depolarization of electrographic seizures in developing hippocampus. J Neurosci. 1993;13(11):4680–9.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Schwartzkroin PA, Kunkel DD, Mathers LH. Development of rabbit hippocampus: anatomy. Dev Brain Res. 1982;2:453–68.

    Article  Google Scholar 

  33. 33.

    Khazipov R, Khalilov I, Tyzio R, Morozova E, Ben-Ari Y, Holmes GL. Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus. Eur J Neurosci. 2004;19(3):590–600.

    PubMed  Article  Google Scholar 

  34. 34.

    Khazipov R, Valeeva G, Khalilov I. Depolarizing GABA and developmental epilepsies. CNS Neurosci Ther. 2015;21(2):83–91.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Dzhala VI, Staley KJ. Excitatory actions of endogenously released GABA contribute to initiation of ictal epileptiform activity in the developing hippocampus. J Neurosci. 2003;23(5):1840–6.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Rheims S, Minlebaev M, Ivanov A, Represa A, Khazipov R, Holmes GL, et al. Excitatory GABA in rodent developing neocortex in vitro. J Neurophysiol. 2008;100(2):609–19.

    PubMed  Article  Google Scholar 

  37. 37.

    Galanopoulou AS, Moshe SL. In search of epilepsy biomarkers in the immature brain: goals, challenges and strategies. Biomark Med. 2011;5(5):615–28.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Avishai-Eliner S, Brunson KL, Sandman CA, Baram TZ. Stressed-out, or in (utero)? Trends Neurosci. 2002;25(10):518–24.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Workman AD, Charvet CJ, Clancy B, Darlington RB, Finlay BL. Modeling transformations of neurodevelopmental sequences across mammalian species. J Neurosci. 2013;33(17):7368–83.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Clancy B, Finlay BL, Darlington RB, Anand KJ. Extrapolating brain development from experimental species to humans. Neurotoxicology. 2007;28(5):931–7.

    PubMed  Article  Google Scholar 

  41. 41.

    Purpura DP. Analysis of axodendritic synaptic organizations in immature cerebral cortex. Ann N Y Acad Sci. 1961;94:604–54.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Purpura DP, Housepian EM. Morphological and physiological properties of chronically isolated immature cortex. Exp Neurol. 1961;4:377–401.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Kinney HC, Brody BA, Kloman AS, Gilles FH. Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants. J Neuropath Exp Neurol. 1988;47:217–34.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Hatten ME. Central nervous system neuronal migration. Annu Rev Neurosci. 1999;22:511–39.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Jabes A, Lavenex PB, Amaral DG, Lavenex P. Quantitative analysis of postnatal neurogenesis and neuron number in the macaque monkey dentate gyrus. Eur J Neurosci. 2010;31(2):273–85.

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Huttenlocher PR, de Court C, Garey LJ, Van der Loos H. Synaptogenesis in human visual cortex–evidence for synapse elimination during normal development. Neurosci Lett. 1982;33(3):247–252.

  47. 47.

    Bourgeois JP. Synaptogenesis, heterochrony and epigenesis in the mammalian neocortex. Acta Paediatr Suppl. 1997;422:27–33.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Hackett TA, Barkat TR, O’Brien BM, Hensch TK, Polley DB. Linking topography to tonotopy in the mouse auditory thalamocortical circuit. J Neurosci. 2011;31(8):2983–95.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005;6(11):877–88.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Kristt DA. Neuronal differentiation in somatosensory cortex of the rat. I. Relationship to synaptogenesis in the first postnatal week. Brain Res. 1978;150(3):467–86.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Miller M, Peters A. Maturation of rat visual cortex. II. A combined Golgi-electron microscope study of pyramidal neurons. J Comp Neurol. 1981;203(4):555–73.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Miller M. Maturation of rat visual cortex. I. A quantitative study of Golgi-impregnated pyramidal neurons. J Neurocytol. 1981;10(5):859–78.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Wise SP, Fleshman JW Jr, Jones EG. Maturation of pyramidal cell form in relation to developing afferent and efferent connections of rat somatic sensory cortex. Neuroscience. 1979;4(9):1275–97.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Tyzio R, Represa A, Jorquera I, Ben-Ari Y, Gozlan H, Aniksztejn L. The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite. J Neurosci. 1999;19:10372–82.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Khazipov R. GABAergic synchronization in epilepsy. Cold Spring Harb Perspect Med. 2016;6(2):a022764.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Leinekugel X, Medina I, Khalilov R, Ben-Ari Y, Khazipov R. Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus. Neuron. 1997;18:243–55.

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science. 2014;343(6171):675–9.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Valeeva G, Valiullina F, Khazipov R. Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro. Front Cell Neurosci. 2013;7:20.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. 59.

    Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11(11):1205–13.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci. 2011;12(9):524–38.

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hubner CA, Represa A, et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science. 2006;314(5806):1788–92.

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Leonzino M, Busnelli M, Antonucci F, Verderio C, Mazzanti M, Chini B. The timing of the excitatory-to-inhibitory GABA switch is regulated by the oxytocin receptor via KCC2. Cell Rep. 2016;15(1):96–103.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Insel TR, Miller LP, Gelhard RE. The ontogeny of excitatory amino acid receptors in rat forebrain–I. N-methyl-d-aspartate and quisqualate receptors. Neuroscience. 1990;35(1):31–43.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Miller LP, Johnson AE, Gelhard RE, Insel TR. The ontogeny of excitatory amino acid receptors in the rat forebrain—II. Kainic acid receptors. Neuroscience. 1990;35:45–51.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    McDonald JW, Johnston MV, Young AB. Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus. Exp Neurol. 1990;110(3):237–47.

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Sheng M, Cummings J, Rolden LA, Jan YN, Jan LY. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature. 1999;368:144–7.

    Article  Google Scholar 

  67. 67.

    Hollmann M, Hartley M, Heinemann S. Ca2+ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition. Science. 1991;252(5007):851–3.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Massicotte G, Baudry M. Brain plasticity and remodeling of AMPA receptor properties by calcium-dependent enzymes. Genet Eng (N Y). 2004;26:239–54.

    CAS  Google Scholar 

  69. 69.

    Talos DM, Fishman RE, Park H, Folkerth RD, Follett PL, Volpe JJ et al. Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex. J Comp Neurol. 2006;497(1):42–60.

  70. 70.

    Hernan AE, Alexander A, Jenks KR, Barry J, Lenck-Santini PP, Isaeva E, et al. Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits. Neurobiol Dis. 2014;63:25–34.

    PubMed  Article  Google Scholar 

  71. 71.

    Velisek L, Kubova H, Veliskova J, Mares P, Ortova M. Action of antiepileptic drugs against kainic acid-induced seizures and automatisms during ontogenesis in rats. Epilepsia. 1992;33(6):987–93.

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Bernaskova K, Mares P. Similar effects of lamotrigine and phenytoin against cortical epileptic foci in immature rats. Physiol Res. 2010;59(1):113–9.

    PubMed  CAS  Google Scholar 

  73. 73.

    Kubova H, Faktorova M, Mares P. Effect of phenobarbital on motor seizures elicited by picrotoxin and bicuculline in rats. Homeost Health Dis. 1991;33(3):113–8.

    PubMed  CAS  Google Scholar 

  74. 74.

    Kerling F, Kasper BS. Efficacy of perampanel: a review of clinical trial data. Acta Neurol Scand Suppl. 2013;197:25–9.

    Article  CAS  Google Scholar 

  75. 75.

    Rosenfeld W, Conry J, Lagae L, Rozentals G, Yang H, Fain R, et al. Efficacy and safety of perampanel in adolescent patients with drug-resistant partial seizures in three double-blind, placebo-controlled, phase III randomized clinical studies and a combined extension study. Eur J Paediatr Neurol. 2015;19(4):435–45.

    PubMed  Article  Google Scholar 

  76. 76.

    Kramer LD, Satlin A, Krauss GL, French J, Perucca E, Ben-Menachem E, et al. Perampanel for adjunctive treatment of partial-onset seizures: a pooled dose-response analysis of phase III studies. Epilepsia. 2014;55(3):423–31.

    PubMed  Article  Google Scholar 

  77. 77.

    Cabral HO, Vinck M, Fouquet C, Pennartz CM, Rondi-Reig L, Battaglia FP. Oscillatory dynamics and place field maps reflect hippocampal ensemble processing of sequence and place memory under NMDA receptor control. Neuron. 2014;81(2):402–15.

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Marshall PJ, Bar-Haim Y, Fox NA. Development of the EEG from 5 months to 4 years of age. Clin Neurophysiol. 2002;113:1199–208.

    PubMed  Article  Google Scholar 

  79. 79.

    Holmes GL. Partial complex seizures in children: an analysis of 69 seizures in 24 patients using EEG FM radiotelemetry and videotape recording. Electroencephalogr Clin Neurophysiol. 1984;57(1):13–20.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Holmes GL. Partial seizures in children. Pediatrics. 1986;77(5):725–31.

    PubMed  CAS  Google Scholar 

  81. 81.

    Nordli DR Jr, Kuroda MM, Hirsch LJ. The ontogeny of partial seizures in infants and young children. Epilepsia. 2001;42(8):986–90.

    PubMed  Article  Google Scholar 

  82. 82.

    Fogarasi A, Janszky J, Tuxhorn I. Peri-ictal lateralizing signs in children: blinded multiobserver study of 100 children < or = 12 years. Neurology. 2006;66(2):271–4.

    PubMed  Article  Google Scholar 

  83. 83.

    Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med. 2017;377(17):1648–56.

    PubMed  Article  Google Scholar 

  84. 84.

    Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol. 1998;44:740–8.

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Spencer S, Huh L. Outcomes of epilepsy surgery in adults and children. Lancet Neurol. 2008;7(6):525–37.

    PubMed  Article  Google Scholar 

  86. 86.

    Dulac O, Milh M, Holmes GL. Brain maturation and epilepsy. Handb Clin Neurol. 2013;111:441–6.

    PubMed  Article  Google Scholar 

  87. 87.

    Camfield P, Camfield C. Epileptic syndromes in childhood: clinical features, outcomes, and treatment. Epilepsia. 2002;43(Suppl 3):27–32.

    PubMed  Article  Google Scholar 

  88. 88.

    Holmes GL. Clinical spectrum of benign focal epilepsies of childhood. Epilepsia. 2000;41(8):1051–2.

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Parisi P, Villa MP, Pelliccia A, Rollo VC, Chiarelli F, Verrotti A. Panayiotopoulos syndrome: diagnosis and management. Neurol Sci. 2007;28(2):72–9.

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Pediatric News. FDA conducts analysis to assess acceptability of extrapolation of antiepileptic drug (AED) effectiveness in adults to children four years of age and older with partial onset seizures (POS). J Pediatr Pharmacol Ther [ 2016 21:[98]. https://www-ncbi-nlm-nih-gov.ezproxy.uvm.edu/pmc/articles/PMC4778704/pdf/i1551-6776-21-1-98.pdf. Accessed 18 Feb 2018.

  91. 91.

    U.S. Department of Health and Human Services. Drugs for treatment of partial onset seizures: full extrapolation of efficacy from adults to pediatric patients 4 years of age and older guidance for industry. 2018. Available from: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm596731.pdf. Accessed 18 Feb 2018.

  92. 92.

    Korff C, Nordli DR Jr. Do generalized tonic-clonic seizures in infancy exist? Neurology. 2005;65(11):1750–3.

    PubMed  Article  Google Scholar 

  93. 93.

    Nordli DR Jr. Idiopathic generalized epilepsies recognized by the International League Against Epilepsy. Epilepsia. 2005;46(Suppl 9):48–56.

    PubMed  Article  Google Scholar 

  94. 94.

    Toulmin H, Beckmann CF, O’Muircheartaigh J, Ball G, Nongena P, Makropoulos A, et al. Specialization and integration of functional thalamocortical connectivity in the human infant. Proc Natl Acad Sci USA. 2015;112(20):6485–90.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Barkat TR, Polley DB, Hensch TK. A critical period for auditory thalamocortical connectivity. Nat Neurosci. 2011;14(9):1189–94.

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Bannister NJ, Benke TA, Mellor J, Scott H, Gurdal E, Crabtree JW, et al. Developmental changes in AMPA and kainate receptor-mediated quantal transmission at thalamocortical synapses in the barrel cortex. J Neurosci. 2005;25(21):5259–71.

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Clawson BC, Durkin J, Aton SJ. Form and function of sleep spindles across the lifespan. Neural Plast. 2016;2016:6936381.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Lenard HG. The development of sleep spindles in the EEG during the first two years of life. Neuropädiatrie. 1970;1:264–76.

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Caraballo RH, Darra F, Fontana E, Garcia R, Monese E, Dalla BB. Absence seizures in the first 3 years of life: an electroclinical study of 46 cases. Epilepsia. 2011;52(2):393–400.

    PubMed  Google Scholar 

  100. 100.

    Marini C, Scheffer IE, Crossland KM, Grinton BE, Phillips FL, McMahon JM, et al. Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families. Epilepsia. 2004;45(5):467–78.

    PubMed  Article  Google Scholar 

  101. 101.

    Marini C, King MA, Archer JS, Newton MR, Berkovic SF. Idiopathic generalised epilepsy of adult onset: clinical syndromes and genetics. J Neurol Neurosurg Psychiatry. 2003;74(2):192–6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Pandolfo M. Pediatric epilepsy genetics. Curr Opin Neurol. 2013;26(2):137–45.

    PubMed  Article  CAS  Google Scholar 

  103. 103.

    Mares P. Models of epileptic seizures in immature rats. Physiol Res. 2012;61(Suppl 1):S103–8.

    PubMed  CAS  Google Scholar 

  104. 104.

    Galiana GL, Gauthier AC, Mattson RH. Eslicarbazepine acetate: a new improvement on a classic drug family for the treatment of partial-onset seizures. Drugs R D 2017.

  105. 105.

    Banach M, Borowicz KK, Czuczwar SJ. Pharmacokinetic/pharmacodynamic evaluation of eslicarbazepine for the treatment of epilepsy. Expert Opin Drug Metab Toxicol. 2015;11(4):639–48.

    PubMed  Article  CAS  Google Scholar 

  106. 106.

    Theodore WH, Narang PK, Holmes MD, Reeves P, Nice FJ. Carbamazepine and its epoxide: relation of plasma levels to toxicity and seizure control. Ann Neurol. 1989;25:194–6.

    PubMed  Article  CAS  Google Scholar 

  107. 107.

    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(2–3):197–206.

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    Soares-da-silva P, Pires N, Bonifacio MJ, Loureiro AI, Palma N, Wright LC. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. Pharmacol Res Perspect. 2015;3(2):e00124.

    PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Hebeisen S, Pires N, Loureiro AI, Bonifacio MJ, Palma N, Whyment A, et al. Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology. 2015;89:122–35.

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Nunes T, Rocha JF, Falcao A, Almeida L, Soares-da-silva P. Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. Epilepsia. 2013;54(1):108–16.

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Bialer M, Soares-da-silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia. 2012;53(6):935–46.

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Package insert for APTIOM. https://www.accessdata.fdagov/drugsatfda_docs/label/2017/022416s009lbl.pdf, 2017.

  113. 113.

    Ben-Menachem E, Gabbai AA, Hufnagel A, Maia J, Almeida L, Soares-da-silva P. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89(2–3):278–85.

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Elger C, Bialer M, Cramer JA, Maia J, Almeida L, Soares-da-silva P. Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia. 2007;48(3):497–504.

    PubMed  Article  CAS  Google Scholar 

  115. 115.

    Gil-Nagel A, Lopes-Lima J, Almeida L, Maia J, Soares-da-silva P. 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(5):281–7.

    PubMed  Article  CAS  Google Scholar 

  116. 116.

    Almeida L, Minciu I, Nunes T, Butoianu N, Falcao A, Magureanu SA, et al. Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol. 2008;48(8):966–77.

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    Singh RP, Asconape JJ. A review of eslicarbazepine acetate for the adjunctive treatment of partial-onset epilepsy. J Cent Nerv Syst Dis. 2011;3:179–87.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Beyreuther BK, Freitag J, Heers C, Krebsfanger N, Scharfenecker U, Stohr T. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13(1):21–42.

    PubMed  Article  CAS  Google Scholar 

  119. 119.

    Patsalos PN, Berry DJ. Pharmacotherapy of the third-generation AEDs: lacosamide, retigabine and eslicarbazepine acetate. Expert Opin Pharmacother. 2012;13(5):699–715.

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Poddar K, Sharma R, Ng YT. Intravenous lacosamide in pediatric status epilepticus: an open-label efficacy and safety study. Pediatr Neurol. 2016;61:83–6.

    PubMed  Article  Google Scholar 

  121. 121.

    Cawello W. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide. Clin Pharmacokinet. 2015;54(9):901–14.

    PubMed  Article  CAS  Google Scholar 

  122. 122.

    Cawello W, Stockis A, Andreas JO, Dimova S. Advances in epilepsy treatment: lacosamide pharmacokinetic profile. Ann N Y Acad Sci. 2014;1329:18–32.

    PubMed  Article  CAS  Google Scholar 

  123. 123.

    Grosso S, Parisi P, Spalice A, Verrotti A, Balestri P. Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy. Eur J Paediatr Neurol. 2014;18(1):55–9.

    PubMed  Article  Google Scholar 

  124. 124.

    Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48(7):1308–17.

    PubMed  Article  CAS  Google Scholar 

  125. 125.

    Halasz P, Kalviainen R, Mazurkiewicz-Beldzinska M, Rosenow F, Doty P, Hebert D, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50(3):443–53.

    PubMed  Article  CAS  Google Scholar 

  126. 126.

    Chung S, Sperling MR, Biton V, Krauss G, Hebert D, Rudd GD, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia. 2010;51(6):958–67.

    PubMed  Article  CAS  Google Scholar 

  127. 127.

    Gavatha M, Ioannou I, Papavasiliou AS. Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy. Epilepsy Behav. 2011;20(4):691–3.

    PubMed  Article  CAS  Google Scholar 

  128. 128.

    Guilhoto LM, Loddenkemper T, Gooty VD, Rotenberg A, Takeoka M, Duffy FH, et al. Experience with lacosamide in a series of children with drug-resistant focal epilepsy. Pediatr Neurol. 2011;44(6):414–9.

    PubMed  Article  Google Scholar 

  129. 129.

    Heyman E, Lahat E, Levin N, Berkovitch M, Gandelman-Marton R. Preliminary efficacy and safety of lacosamide in children with refractory epilepsy. Eur J Paediatr Neurol. 2012;16(1):15–9.

    PubMed  Article  Google Scholar 

  130. 130.

    Rastogi RG, Ng YT. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol. 2012;27(4):492–5.

    PubMed  Article  Google Scholar 

  131. 131.

    McGinnis E, Kessler SK. Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort. Epilepsia. 2016;57(9):1416–25.

    PubMed  Article  CAS  Google Scholar 

  132. 132.

    Verrotti A, Loiacono G, Pizzolorusso A, Parisi P, Bruni O, Luchetti A, et al. Lacosamide in pediatric and adult patients: comparison of efficacy and safety. Seizure. 2013;22(3):210–6.

    PubMed  Article  Google Scholar 

  133. 133.

    Pasha I, Kamate M, Didagi SK. Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy. Pediatr Neurol. 2014;51(4):509–14.

    PubMed  Article  Google Scholar 

  134. 134.

    Buck ML, Goodkin HP. Use of lacosamide in children with refractory epilepsy. J Pediatr Pharmacol Ther. 2012;17(3):211–9.

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Division of Clinical Pharmacology. Clinical Pharmacology Review. Available from:https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM572944.pdf. Accessed 18 Feb 2018.

  136. 136.

    Hanada T, Hashizume Y, Tokuhara N, Takenaka O, Kohmura N, Ogasawara A, et al. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia. 2011;52(7):1331–40.

    PubMed  Article  CAS  Google Scholar 

  137. 137.

    Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand Suppl. 2013;197:19–24.

    Article  CAS  Google Scholar 

  138. 138.

    Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, et al. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307. Epilepsia. 2013;54(1):126–34.

    PubMed  Article  CAS  Google Scholar 

  139. 139.

    Patsalos PN, Gougoulaki M, Sander JW. Perampanel serum concentrations in adults with epilepsy: effect of dose, age, sex, and concomitant anti-epileptic drugs. Ther Drug Monit. 2016;38(3):358–64.

    PubMed  Article  CAS  Google Scholar 

  140. 140.

    Faulkner MA. Spotlight on perampanel in the management of seizures: design, development and an update on place in therapy. Drug Des Devel Ther. 2017;11:2921–30.

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Faulkner MA. Perampanel: a new agent for adjunctive treatment of partial seizures. Am J Health Syst Pharm. 2014;71(3):191–8.

    PubMed  Article  CAS  Google Scholar 

  142. 142.

    Villanueva V, Majid O, Nabangchang C, Yang H, Laurenza A, Ferry J, et al. Pharmacokinetics, exposure-cognition, and exposure-efficacy relationships of perampanel in adolescents with inadequately controlled partial-onset seizures. Epilepsy Res. 2016;127:126–34.

    PubMed  Article  CAS  Google Scholar 

  143. 143.

    French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia. 2013;54(1):117–25.

    PubMed  Article  CAS  Google Scholar 

  144. 144.

    French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79(6):589–96.

    PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Lagae L, Villanueva V, Meador KJ, Bagul M, Laurenza A, Kumar D, et al. Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: a randomized study evaluating behavior, efficacy, and safety. Epilepsia. 2016;57(7):1120–9.

    PubMed  Article  CAS  Google Scholar 

  146. 146.

    Ko D, Yang H, Williams B, Xing D, Laurenza A. Perampanel in the treatment of partial seizures: time to onset and duration of most common adverse events from pooled Phase III and extension studies. Epilepsy Behav. 2015;48:45–52.

    PubMed  Article  Google Scholar 

  147. 147.

    Gillard M, Fuks B, Leclercq K, Matagne A. Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol. 2011;664(1–3):36–44.

    PubMed  Article  CAS  Google Scholar 

  148. 148.

    Coppola G, Iapadre G, Operto FF, Verrotti A. New developments in the management of partial-onset epilepsy: role of brivaracetam. Drug Des Devel Ther. 2017;11:643–57.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  149. 149.

    Rolan P, Sargentini-Maier ML, Pigeolet E, Stockis A. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men. Br J Clin Pharmacol. 2008;66(1):71–5.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. 150.

    Sargentini-Maier ML, Rolan P, Connell J, Tytgat D, Jacobs T, Pigeolet E, et al. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males. Br J Clin Pharmacol. 2007;63(6):680–8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. 151.

    Sargentini-Maier ML, Espie P, Coquette A, Stockis A. Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects. Drug Metab Dispos. 2008;36(1):36–45.

    PubMed  Article  CAS  Google Scholar 

  152. 152.

    Nicolas JM, Chanteux H, Rosa M, Watanabe S, Stockis A. Effect of gemfibrozil on the metabolism of brivaracetam in vitro and in human subjects. Drug Metab Dispos. 2012;40(8):1466–72.

    PubMed  Article  CAS  Google Scholar 

  153. 153.

    Stockis A, Watanabe S, Rouits E, Matsuguma K, Irie S. Brivaracetam single and multiple rising oral dose study in healthy Japanese participants: influence of CYP2C19 genotype. Drug Metab Pharmacokinet. 2014;29(5):394–9.

    PubMed  Article  CAS  Google Scholar 

  154. 154.

    Kwan P, Trinka E, Van PW, Rektor I, Johnson ME, Lu S. 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.

    PubMed  Article  CAS  Google Scholar 

  155. 155.

    Klein P, Schiemann J, Sperling MR, Whitesides J, Liang W, Stalvey T, 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.

    PubMed  Article  CAS  Google Scholar 

  156. 156.

    Biton V, Berkovic SF, Abou-Khalil B, Sperling MR, Johnson ME, Lu S. 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.

    PubMed  Article  CAS  Google Scholar 

  157. 157.

    Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia. 2014;55(1):47–56.

    PubMed  Article  CAS  Google Scholar 

  158. 158.

    French JA, Costantini C, Brodsky A, von Rosenstiel RP. Adjunctive brivaracetam for refractory partial-onset seizures: a randomized, controlled trial. Neurology. 2010;75(6):519–25.

    PubMed  Article  CAS  Google Scholar 

  159. 159.

    Van Paesschen W, Hirsch E, Johnson M, Falter U, von Rosenstiel P. 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.

    PubMed  Article  CAS  Google Scholar 

  160. 160.

    Tian X, Yuan M, Zhou Q, Wang X. The efficacy and safety of brivaracetam at different doses for partial-onset epilepsy: a meta-analysis of placebo-controlled studies. Expert Opin Pharmacother. 2015;16(12):1755–67.

    PubMed  Article  CAS  Google Scholar 

  161. 161.

    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology. 2016;86(14):1344–52.

    PubMed  Article  Google Scholar 

  162. 162.

    Schoemaker R, Wade JR, Stockis A. Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years. Eur J Clin Pharmacol. 2017;73(6):727–33.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Gregory L. Holmes.

Ethics declarations

Funding

No financial support was received for this study.

Conflict of interest

Dr. A. Arzimanoglou occasionally serves as an advisory board member, consultant or lecturer for Eisai, GW Pharma, Shire, Takeda and UCB and has received royalties. He has also received research grants from UCB and Caixa Bank. Dr. S. Shinnar serves on two data safety monitoring boards (DSMBs) for UCB Pharma and one for Eisai. He has received personal compensation for serving on the Scientific Advisory Board for UCB, for consulting for Mallinckrod, Neurelis, Upsher-Smith and Xeris. He has received royalties for editing a book. Dr. N. D’Cruz serves as a coordinator and industry representative to the PEACE initiative; he was previously an employee at UCB and Cyberonics, and is currently an independent industry consultant. Dr. G.L. Holmes is on DSMBs for Eisai, UCB Pharma, INCYS, Zogenix and the National Heart, Lung and Blood Institute (NHLBI). Dr. D. Nordli, Jr. has received an honorarium from Eisai for consulting work and has received royalties for editing a book.

Additional information

This article is dedicated to John (Jack) M. Pellock, who was critical in the origin of the PEACE initiative and actively co-chaired it during its inception and implementation. The authors would like to acknowledge his major contribution in the field of pediatric epilepsy, his pioneering work in antiepileptic drug therapy, his constant efforts in the service of healthcare and education, his respect for sick children and their families, and his collegiality and support of his colleagues.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Arzimanoglou, A., D’Cruz, O., Nordli, D. et al. A Review of the New Antiepileptic Drugs for Focal-Onset Seizures in Pediatrics: Role of Extrapolation. Pediatr Drugs 20, 249–264 (2018). https://doi.org/10.1007/s40272-018-0286-0

Download citation