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.
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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.
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.
Hauser WA. Epidemiology of epilepsy in children. Neurosurg Clin N Am. 1995;6(3):419–29.
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.
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.
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.
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.
Amann JP, Glauser T, Chiron C. Developing antiepileptic drugs in children: balancing protection and access. Handb Clin Neurol. 2013;111:741–6.
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.
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.
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.
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.
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.
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.
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.
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.
Cowan LD, Bodensteiner JB, Leviton A, Doherty L. Prevalence of the epilepsies in children and adolescents. Epilepsia. 1989;30(1):94–106.
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.
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.
Sillanpää M, Jalava M, Shinnar S. Epilepsy syndromes in patients with childhood-onset seizures in Finland. Pediatr Neurol. 1992;21:533–7.
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.
Beydoun A. Monotherapy trials of new antiepileptic drugs. Epilepsia. 1997;38(Suppl 9):S21–31.
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.
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.
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.
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.
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.
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.
Kandel ER, Spencer WA. Excitation and inhibition of single pyramidal cells during hippocampal seizures. Exp Neurol. 1961;4:163–79.
Sawa M, Maruyama N, Kaji S. Intracellular potential recording during electrically induced seizures. Electroencephalogr Clin Neurophysiol. 1963;15:209–20.
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.
Schwartzkroin PA, Kunkel DD, Mathers LH. Development of rabbit hippocampus: anatomy. Dev Brain Res. 1982;2:453–68.
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.
Khazipov R, Valeeva G, Khalilov I. Depolarizing GABA and developmental epilepsies. CNS Neurosci Ther. 2015;21(2):83–91.
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.
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.
Galanopoulou AS, Moshe SL. In search of epilepsy biomarkers in the immature brain: goals, challenges and strategies. Biomark Med. 2011;5(5):615–28.
Avishai-Eliner S, Brunson KL, Sandman CA, Baram TZ. Stressed-out, or in (utero)? Trends Neurosci. 2002;25(10):518–24.
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.
Clancy B, Finlay BL, Darlington RB, Anand KJ. Extrapolating brain development from experimental species to humans. Neurotoxicology. 2007;28(5):931–7.
Purpura DP. Analysis of axodendritic synaptic organizations in immature cerebral cortex. Ann N Y Acad Sci. 1961;94:604–54.
Purpura DP, Housepian EM. Morphological and physiological properties of chronically isolated immature cortex. Exp Neurol. 1961;4:377–401.
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.
Hatten ME. Central nervous system neuronal migration. Annu Rev Neurosci. 1999;22:511–39.
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.
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.
Bourgeois JP. Synaptogenesis, heterochrony and epigenesis in the mammalian neocortex. Acta Paediatr Suppl. 1997;422:27–33.
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.
Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005;6(11):877–88.
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.
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.
Miller M. Maturation of rat visual cortex. I. A quantitative study of Golgi-impregnated pyramidal neurons. J Neurocytol. 1981;10(5):859–78.
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.
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.
Khazipov R. GABAergic synchronization in epilepsy. Cold Spring Harb Perspect Med. 2016;6(2):a022764.
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.
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.
Valeeva G, Valiullina F, Khazipov R. Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro. Front Cell Neurosci. 2013;7:20.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Massicotte G, Baudry M. Brain plasticity and remodeling of AMPA receptor properties by calcium-dependent enzymes. Genet Eng (N Y). 2004;26:239–54.
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.
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.
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.
Bernaskova K, Mares P. Similar effects of lamotrigine and phenytoin against cortical epileptic foci in immature rats. Physiol Res. 2010;59(1):113–9.
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.
Kerling F, Kasper BS. Efficacy of perampanel: a review of clinical trial data. Acta Neurol Scand Suppl. 2013;197:25–9.
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.
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.
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.
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.
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.
Holmes GL. Partial seizures in children. Pediatrics. 1986;77(5):725–31.
Nordli DR Jr, Kuroda MM, Hirsch LJ. The ontogeny of partial seizures in infants and young children. Epilepsia. 2001;42(8):986–90.
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.
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.
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.
Spencer S, Huh L. Outcomes of epilepsy surgery in adults and children. Lancet Neurol. 2008;7(6):525–37.
Dulac O, Milh M, Holmes GL. Brain maturation and epilepsy. Handb Clin Neurol. 2013;111:441–6.
Camfield P, Camfield C. Epileptic syndromes in childhood: clinical features, outcomes, and treatment. Epilepsia. 2002;43(Suppl 3):27–32.
Holmes GL. Clinical spectrum of benign focal epilepsies of childhood. Epilepsia. 2000;41(8):1051–2.
Parisi P, Villa MP, Pelliccia A, Rollo VC, Chiarelli F, Verrotti A. Panayiotopoulos syndrome: diagnosis and management. Neurol Sci. 2007;28(2):72–9.
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:. https://www-ncbi-nlm-nih-gov.ezproxy.uvm.edu/pmc/articles/PMC4778704/pdf/i1551-6776-21-1-98.pdf. Accessed 18 Feb 2018.
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.
Korff C, Nordli DR Jr. Do generalized tonic-clonic seizures in infancy exist? Neurology. 2005;65(11):1750–3.
Nordli DR Jr. Idiopathic generalized epilepsies recognized by the International League Against Epilepsy. Epilepsia. 2005;46(Suppl 9):48–56.
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.
Barkat TR, Polley DB, Hensch TK. A critical period for auditory thalamocortical connectivity. Nat Neurosci. 2011;14(9):1189–94.
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.
Clawson BC, Durkin J, Aton SJ. Form and function of sleep spindles across the lifespan. Neural Plast. 2016;2016:6936381.
Lenard HG. The development of sleep spindles in the EEG during the first two years of life. Neuropädiatrie. 1970;1:264–76.
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.
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.
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.
Pandolfo M. Pediatric epilepsy genetics. Curr Opin Neurol. 2013;26(2):137–45.
Mares P. Models of epileptic seizures in immature rats. Physiol Res. 2012;61(Suppl 1):S103–8.
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.
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.
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.
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.
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.
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.
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.
Bialer M, Soares-da-silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia. 2012;53(6):935–46.
Package insert for APTIOM. https://www.accessdata.fdagov/drugsatfda_docs/label/2017/022416s009lbl.pdf, 2017.
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.
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.
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.
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.
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.
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.
Patsalos PN, Berry DJ. Pharmacotherapy of the third-generation AEDs: lacosamide, retigabine and eslicarbazepine acetate. Expert Opin Pharmacother. 2012;13(5):699–715.
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.
Cawello W. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide. Clin Pharmacokinet. 2015;54(9):901–14.
Cawello W, Stockis A, Andreas JO, Dimova S. Advances in epilepsy treatment: lacosamide pharmacokinetic profile. Ann N Y Acad Sci. 2014;1329:18–32.
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.
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.
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.
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.
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.
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.
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.
Rastogi RG, Ng YT. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol. 2012;27(4):492–5.
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.
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.
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.
Buck ML, Goodkin HP. Use of lacosamide in children with refractory epilepsy. J Pediatr Pharmacol Ther. 2012;17(3):211–9.
Division of Clinical Pharmacology. Clinical Pharmacology Review. Available from:https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM572944.pdf. Accessed 18 Feb 2018.
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.
Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand Suppl. 2013;197:19–24.
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.
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.
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.
Faulkner MA. Perampanel: a new agent for adjunctive treatment of partial seizures. Am J Health Syst Pharm. 2014;71(3):191–8.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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