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

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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.

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Authors and Affiliations

  1. Department of Clinical Epileptology, Sleep Disorders and Functional Pediatric Neurology, University Hospitals of Lyon (HCL), Lyon, France

    Alexis Arzimanoglou

  2. Sección Epilepsia, Sueño y Neurofisiología, Servicio Neurología, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain

    Alexis Arzimanoglou

  3. Consulting and Neurological Services, Chapel Hill, NC, USA

    O’Neill D’Cruz

  4. Division of Pediatric Neurology, Children’s Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Douglas Nordli

  5. Departments of Neurology, Pediatrics and Epidemiology and Population Health, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA

    Shlomo Shinnar

  6. Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, VT, USA

    Gregory L. Holmes

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  1. Alexis Arzimanoglou
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  2. O’Neill D’Cruz
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  3. Douglas Nordli
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  4. Shlomo Shinnar
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  5. Gregory L. Holmes
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Consortia

For the Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE)

Corresponding author

Correspondence to Gregory L. Holmes.

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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.

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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

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