Publish in this journal
Journal Information
Vol. 91. Issue 6.
Pages 415.e1-415.e10 (01 December 2019)
Visits
0
Vol. 91. Issue 6.
Pages 415.e1-415.e10 (01 December 2019)
Special Article
DOI: 10.1016/j.anpede.2019.09.005
Open Access
New anti-epileptic drugs in paediatrics
Nuevos fármacos antiepilépticos en Pediatría
Visits
0
Ignacio Málagaa,
Corresponding author
, Rocío Sánchez-Carpinterob, Susana Roldánc, Julio Ramos-Lizanad, Juan José García-Peñase
a Unidad de Neuropediatría, Hospital Universitario Central de Asturias, Oviedo, Spain
b Unidad de Neuropediatría, Clínica Universitaria de Navarra, Pamplona, Spain
c Servicio de Neuropediatría, Hospital Universitario Virgen de las Nieves, Granada, Spain
d Hospital de Torrecárdenas, Almería, Spain
e Unidad de Epilepsia, Sección de Neuropediatría, Hospital Universitario Niño Jesús, Madrid, Spain
This item has received
0
Visits

Under a Creative Commons license
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Figures (1)
Tables (3)
Table 1. Main antiepileptic drugs and year of introduction in Europe (authorization of the European Medicines Agency), in chronological order.
Table 2. Main characteristics of third-generation AEDs used in the paediatric population.
Table 3. Main advantages and disadvantages of third-generation antiepileptic drugs in the paediatric population.
Show moreShow less
Abstract

It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5–0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of anti-epileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology, the extrapolation of the efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population.

Keywords:
Drugs
Epilepsy
Paediatrics
Convulsion
Resumen

Se estima que unos 70 millones de personas padecen epilepsia a nivel mundial de los cuales más de la mitad son niños, en los que la prevalencia estimada se sitúa en torno al 0,5-0,8%. Aunque existen diversas terapias, el tratamiento de la epilepsia se basa mayoritariamente en fármacos, que en función de su año de comercialización se clasifican como de primera, segunda o tercera generación. En el presente artículo se revisan las principales características de los fármacos antiepilépticos de última generación (lacosamida, acetato de eslicarbazepina, brivaracetam, perampanel, retigabina, everolimus y cannabidiol) que, con excepción de la retigabina (ya no está comercializada), se consideran seguros y efectivos en población pediátrica. El everolimus y el cannabidiol tienen indicaciones muy concretas (esclerosis tuberosa, síndrome de Dravet y síndrome de Lennox Gastaut) mientras que el resto están indicados en el manejo de crisis de origen focal en niños a partir de 4 años. Estas nuevas moléculas han sido desarrolladas para aportar un perfil farmacocinético y de tolerancia superior a los fármacos previamente disponibles y es previsible que a medida que aumente su uso, se vaya perfilando y ampliando su verdadero potencial. Además, por primera vez en epileptología pediátrica, se ha utilizado la extrapolación de datos de efectividad en adultos (junto con estudios de seguridad y farmacocinética específicos en población pediátrica), para acelerar la aprobación de uso en población infantil.

Palabras clave:
Fármacos
Epilepsia
Pediatría
Convulsión
Full Text
Introduction

It is estimated that approximately 70 million people worldwide suffer from epilepsy, of who more than half are of paediatric age.1–3 Thus, this is a relatively frequent neurologic disorder in children that impairs the quality of life of patients and their families, poses a substantial burden to society and with a significant economic impact on health care systems.1

The term epilepsy encompasses a broad and heterogeneous range of disorders and syndromes with a high variability in terms of the aetiology, severity and course of disease. All of the above has significant implications in terms of diagnosis and management, which, depending on the geographical area, the complexity of the case and the availability of health care providers, are carried out at different levels of specialization (general practitioners, general paediatricians, neurologists, paediatric neurologists or paediatric epileptologists).

Epilepsy is a disease that is clearly influenced by the level of development of a society, as both its incidence and prevalence are higher in developing countries (it is estimated that between 75% and 80% of new cases occur in these regions).3,4 The incidence of seizures is highest in the first year of life (100 cases/100000) and decreases with age until reaching a rate of approximately 20 cases/100000 in adolescence. The estimated overall prevalence in the paediatric age group (<16 years) is of 0.5%–0.8%,5,6 with a predominance of focal forms (59%–63%) and a lesser frequency of generalised epilepsy (12%–29%), although in 20% of cases the classification may vary in the same patient during the course of the disease.5,7

In children as well as adults, the treatment of epilepsy is mostly based on the use of drugs (either in monotherapy or combined therapy), and the remaining approaches (surgery, neuromodulation, ketogenic diet) are used much less frequently. In addition, most patients managed with nonpharmacological approaches require drugs as adjuvant treatment to achieve optimal seizure control.

Antiepileptic drugs are molecules that act at different levels of the synapse with the aim of modifying the excitatory and/or inhibitory responses through different mechanisms (sodium or calcium channels, GABA receptors, glutamate, etc). Their mechanisms of action are diverse, and are not even fully understood in some of the drugs (Fig. 1), and there are excellent review articles on the subject.8–10 At present, there are more than 25 drugs classified based on the year they were authorised for distribution as first-, second- or third-generation (Table 1).11,12

Figure 1.

Simplified representation of the mechanism of action of the main antiepileptic drugs in the synapsis. GABA-T: GABA transaminase (enzyme inducing the degradation of GABA). GAT-1: GABA transporter type 1 (removes GABA from the synaptic cleft after the synapse).

(0.51MB).
Table 1.

Main antiepileptic drugs and year of introduction in Europe (authorization of the European Medicines Agency), in chronological order.

  Drug  International abbreviation  Date of introduction in market 
First generationBromide  –  1857 
Phenobarbital  PB  1912 
Phenytoin  PHT  1960 
Primidone  PRM  1960 
Sulthiame  STM  1960 
Carbamazepine  CBZ  1965 
Valproate  VPA  1970 
Second generationClobazam  CLB  1979 
Vigabatrin  VGB  1989 
Oxcarbazepine  OXC  1990 
Lamotrigine  LTG  1991 
Gabapentin  GBP  1994 
Felbamate  FBM  1994 
Topiramate  TPM  1995 
Tiagabine  TGB  1996 
Levetiracetam  LEV  2000 
Pregabalin  PGB  2005 
Zonisamide  ZNS  2007 
Stiripentol  STP  2007 
Rufinamide  RUF  2007 
Third generationEslicarbazepine (acetate)  ESL  2010 
Lacosamide  LCM  2010 
Retigabine/ezogabine  RTG/EZG  2011 
Perampanel  PER  2012 
Everolimus  EVR  2017 
Brivaracetam  BRV  2018 
Cannabidiol  CBD  2019 

The management of epilepsy in the paediatric age group has specific characteristics, since many of the forms of epilepsy in this population are different from those found in adults (including most of the epileptic syndromes), and so does the management of antiepileptic drugs and the potential adverse events or sequelae derived from their use, as they differ from those in adults.11 On the other hand, there are also similarities with the management in adults, specifically, the disease progression and response to treatment of focal-onset seizures is similar in children aged 2 or more years and in adult patients, which makes it possible to extrapolate data from adult studies to expedite authorization of new drugs for use in children.13

Obtaining authorization for use of new antiepileptic drugs in the paediatric population usually takes years, which encourages off-label use in this age group. This results in a lack of safety for the patient (absence of validated data on the dosage, safety and tolerability) and ethical and legal problems for the prescriber.13 Extrapolation, a term initially established by the Food and Drug Administration (FDA) in 1994 and now used and validated at the international level, may be used to shorten the time elapsed between authorization of a drug for use in adults and its authorization for use in children.13,14 In paediatrics, the aim of extrapolation is to guarantee the efficient use of data obtained in adults in the development of drugs for use in the paediatric population. Extrapolation is defined as “extending information and conclusions available from studies in one or more subgroups of the patient population (source population(s)), or in related conditions or with related medicinal products, in order to make inferences for another subgroup of the population (target population), or condition or product, thus reducing the amount of, or general need for, additional evidence generation (types of studies, design modifications, number of patients required) needed to reach conclusions.”13,15 In order to extrapolate information on drugs, several conditions must be assumed to be true, the most important of which are: (a) that the course of disease is similar in adults children, (b) that the response to treatment is similar in adults and children, and (c) that the response to exposure to the drug is similar in both populations.13,15

In epilepsy, extrapolation cannot be performed generally, as there are significant differences between children and adults in its aetiology, types of epileptic syndromes and natural history, but similarities have been established in focal-onset seizures between children aged 4 or more years and adults.13 Nevertheless, it is important to take into account that while it is possible to assume similarities in efficacy, it is not possible to extrapolate data on other aspects such as dosage, pharmacokinetics or safety, and therefore studies in the paediatric age group continue to be necessary.

In this study, we will merely review the main novelties in pharmacological management of epilepsy in the paediatric age group. This last generation of drugs is the first to include molecules whose effectiveness in children has not been demonstrated through specific double-blind randomised controlled clinical trials, but based on the extrapolation from data obtained in adult studies (eslicarbazepine acetate, brivaracetam, lacosamide, perampanel).

Eslicarbazepine acetate (ESL)

Eslicarbazepine acetate is a third-generation drug in the carboxamide family (CBZ, OXC) that acts by blocking voltage-gated sodium channels, resulting in a slow inactivation of neuron excitability. It was initially authorised for use in adults in Europe by the EMA in 2010 and later in 2013 in the United States by the FDA for adjuvant treatment of focal-onset seizures with or without secondary generalization. This indication was subsequently extended to include use as monotherapy. Since 2017 it has been authorised for use in the paediatric population for adjuvant treatment of focal-onset seizures with or without secondarily generalised seizures in children aged 4 or more years (FDA) or children aged 6 or more years (EMA), making it the first antiepileptic drug approved for use in children based on extrapolation. The main advantages of ESL are its administration as a single daily dose (which facilitates adherence to treatment), the absence of significant interactions with other drugs and a favourable safety profile, as no significant changes in haematology or chemistry parameters have been described. In this regard, hyponatraemia tends to be less frequent in comparison with OXC.11,16 The adverse effects seem to be dose-dependent and are presented in Table 2. This drug does not seem to cause cognitive or behavioural adverse effects in children.17

Table 2.

Main characteristics of third-generation AEDs used in the paediatric population.

Name  Laboratory  Therapeutic target  Indication in children (starting age)  Recommended dosage  Route of administration  Most frequent adverse effects 
Eslicarbazepine acetate (ESL)  Sunovion Pharmaceuticals/BIAL-Portela USA.  Voltage-gated sodium channel inhibition  Adjuvant treatment for focal-onset seizures (with or without secondary generalization) in children ≥4 years (FDA, 2017) or ≥6 years (EMA, 2016)  Starting dose: 10–20mg/kg/day in a single daily dose.Increases of 200–400mg every 1–2 weeks.Maintenance dose: 20–60mg/kg/dayMaximum dose: 1200mg/day.Weight >60kg: adult dosage.  Oral  In 80% of patients. Dizziness, somnolence, nausea, diplopia, headache, vomiting, changes in coordination, blurry vision, vertigo and fatigue. 
Lacosamide (LCM)  UCB Inc.  Modulation of slow inactivation of sodium channels  Use as monotherapy or adjuvant therapy for treatment of focal-onset seizures (with or without secondary generalization) in children ≥4 years (EMA, FDA, 2017)  Starting dose: 2mg/kg/day (divided in 2 daily doses). Weekly increases of 2mg/kg/day.Maintenance dose:Weight of 11–30kg: 6–12mg/kg/dayWeight 30–50kg: 4–8mg/kg/dayWeight ≥50kg:Starting dose: 100mg/day (divided in 2 daily doses). Weekly increases of 100mg/day.Maintenance dose:Monotherapy: 300–400mg/dayAdjuvant therapy: 200–400mg/day.  Oral, IV  In 30%–59% of patients. Nausea, vomiting, instability, dizziness, nystagmus, weakness, headache. 
Retigabine (RTG)/ezogabine (EZG)  GlaxoSmithKline  Modulation of sodium channels and GABA receptors  No  –  Oral  Authorization withdrawn by FDA and EMA due to adverse events related to the pigmentation of skin and the retina. 
Perampanel (PER)  Eisai Inc.  Non-competitive AMPA glutamate receptor antagonist  In children >12 years as monotherapy (FDA, 2017) or adjuvant therapy (FDA, EMA, 2012) for focal-onset seizures with or without secondary generalizationIn children >4 years for use as monotherapy or adjuvant treatment for focal-onset seizures with or without secondary generalization (FDA, 2018)  Starting dose:2mg/day as a single daily doseIncreases weekly (or further apart) in 2mg increments based on response.Maintenance dose:8mg/day.Maximum dose: 12mg/day)  Oral  In up to 70% of patients. Dizziness, somnolence, aggressiveness, irritability, loss of appetite, rhinitis. 
Everolimus (EVR)  Novartis  mTOR pathway inhibitor  Adjuvant treatment in children >2 years with drug-resistant focal-onset seizures associated withTSC (EMA, 2017) (FDA, 2018)  Starting dose: 5mg/m2 as a single daily doseProgressive adjustments until reaching plasma levels of 5–15ng/mL  Oral  In 95% of patients. Stomatitis, upper respiratory tract infections, nasopharyngitis, sinusitis, cough, pneumonia, urinary tract infection, high blood pressure, hypercholesterolemia, amenorrhoea, headache, diarrhoea or vomiting, rash, fever, anorexia. 
Brivaracetam (BRV)  UCB  Synaptic vesicle protein 2A (SV2A)  Treatment of children >4 years with focal-onset seizures as monotherapy (FDA) or adjuvant treatment (FDA, EMA)  Starting dose: 1–2mg/kg/day (divided in 2 daily doses)Progressive adjustments until achieving the desired effectMaintenance dose: 1–5mg/kg/dayWeight ≥50 kg:Starting dose: 20–100mg/day. Maximum dose: 200mg/day.  Oral, IV  In 32% of patients. Somnolence, headache, dizziness, fatigue, nausea, nasopharyngitis, irritability, insomnia, anxiety, depression 
Cannabidiol (CBD)  GW Pharmaceuticals Inc.  Probable modulation of GABA-A receptor  Treatment of seizures inpatients >2 years with Dravet syndrome or Lennox-Gastaut syndrome (FDA, 2018)Adjuvant treatment (in association with CLB) of seizures in patients >2 years with Dravet syndrome or Lennox-Gastaut syndrome (EMA, 2019)  Starting dose: 5mg/kg/day (divided in 2 daily doses).Weekly increase by 5mg/kg/day until desired effect is achievedMaintenance dose: 20mg/kg/day.  Oral  In 79% of patients. Sedation, fatigue, anorexia, diarrhoea, changes in liver enzymes (especially in combination with VPA and CLB) 
Lacosamide (LCM)

Lacosamide is a functionalised amino acid that acts on the neuron by enhancing selective slow inactivation of voltage-gated sodium channels. It does not affect rapid inactivation, so it is believed to modulate the pathological neuronal hyperexcitability without altering the physiological function of the cell.18 It was first authorised for use in adults aged more than 17 years by the FDA (2008) for adjuvant treatment of focal-onset seizures with or without secondary generalization. Since 2017, it has been authorised by the EMA and the FDA for use as monotherapy or add-on treatment in children from age 4 years. Lacosamide has the advantage of being an effective, safe and well-tolerated drug in the paediatric population, with little interaction with other drugs and that may delivered by both the enteral and parenteral routes. Furthermore, based on case series published in the past 5 years, in the future it could be considered a safe and effective treatment for status epilepticus and refractory status epilepticus in the paediatric age group.19Table 2 presents the most frequent adverse events, revealing a favourable neurotoxicity profile: depression in 9.5%, memory changes in 7.4% and other forms of cognitive impairment in 4.3%.11,20

Retigabine (RTG)/ezogabine (EZG)

Retigabine (international nonproprietary name) or ezogabine (United States adopted name) exhibits a unique mechanism of action among antiepileptic drugs, as it acts by activating KCNQ2-5 potassium channels, although it also modulates GABA receptors.4,10 This drug was authorised by the FDA and the EMA in 2011 for treatment of focal epilepsy with or without secondarily generalised seizures in adults. Later on, authorization was withdrawn by both agencies (FDA in 2017, EMA in 2018) upon request from manufacturer due to adverse effects involving skin pigmentation and the retina, so it is not currently available. It was never authorised for use in the paediatric population, and there is a single article in the paediatric literature describing successful treatment of a girl aged 8 years with ring chromosome 20 syndrome. The region where this fusion occurs most frequently is q13.3, where the KCNQ2 gene is located.21

Perampanel (PER)

Perampanel is one of the drugs authorised most recently for treatment of epilepsy in children (FDA 2018), although it has been authorised for treatment of adults and children aged 12 or more years since 2012. It acts as a highly selective non-competitive AMPA glutamate receptor antagonist (localized at excitatory synapses, post-synaptically), which makes its mechanism of action unique among the antiepileptic drugs. The inhibition results from the modulation of fast excitatory synaptic transmission.22,23 In adults and children aged more than 12 years, it is indicated for treatment of focal-onset seizures with or without secondary generalization (FDA and EMA, 2012) and of generalised tonic-clonic seizures (EMA and FDA, 2015). In 2018, the FDA expanded the indication to children aged 4 or more years with focal-onset seizures with or without secondary generalization based on extrapolated data after performance of safety and pharmacokinetic studies. Authorization in this age group by the EMA is still pending.13 Furthermore, several studies in children and adolescents have demonstrated its effectiveness in the treatment of focal-onset seizures.22 The main advantages of PER are the low incidence of cognitive side effects, its route of administration, the single daily dose that facilitates adherence to treatment and its favourable risk/benefit ratio. Adverse effects are more frequent in children aged more than 12 years compared to younger children, and they have been described in up to 70% of patients. Psychiatric changes are among the most significant adverse effects it causes (Table 2), including aggressiveness and irritability, which seem to be dose-dependent and have been described in 8.2% to 14% of treated children. They are most frequent in the first 6 weeks of treatment and in patients with psychiatric comorbidities, such as ADHD or personality disorders.10,22

Everolimus (EVR)

Everolimus is a drug that in paediatric neurology is mainly used for management of diseases secondary to tuberous sclerosis complex (TSC), a neurocutaneous syndrome with a low prevalence (1 in 6000 births) that is, however, characterised by significant morbidity involving multiple systems and specifically the central nervous system. It is an inhibitor of complex 1 of mTOR (the mammalian target of rapamycin) indicated in patients with TSC for management of subependymal giant cell astrocytoma (SEGA), renal angiomyolipomas and epilepsy. Epilepsy is the most frequent disorder found in patients with TSC (85% of patients), usually with onset in the first year of life (2 out of 3 cases), manifesting either with focal-onset seizures or epileptic spasms. In more than 60% of patients, the seizures are drug-resistant.24 Evidence of its usefulness as an anticonvulsant first emerged during clinical trials of EVR for treatment of SEGA.25,26 Later on, based on the findings of the EXIST-3 trial (an international prospective multicentre double-blind randomised controlled study, n=366),27) the EMA (2017) and the FDA (2018) authorise the indication for use as an adjuvant antiepileptic drug in adults and children aged at least 2 years with drug-resistant focal-onset seizures associated with TSC. Treatment with EVR needs to be adjusted as needed while monitoring its plasma levels, and is likely to produce adverse events (Table 2), with stomatitis being the complication that most frequently leads to a dose reduction or discontinuation of the drug.11,27

Brivaracetam (BRV)

Brivaracetam is a modified analogue of levetiracetam (LEV), so it has a similar mechanism of action through binding to synaptic vesicle protein 2A (SV2A), although BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV.10,28 Its also exhibits partial inhibition of voltage-gated sodium channels. Brivaracetam was first authorised for adjuvant treatment of focal-onset seizures in patients aged 16 or more years in 2016 (FDA, EMA), with its indications later expanding to use as monotherapy (2017) and finally to use in the paediatric population aged 4 or more years (2018) based on extrapolation.

The main advantages of BRV is that it is a safe and effective drug that can be administered enterally or parenterally and that it is very promising due to the high effectiveness it has exhibited against different types of seizures in animal models.13 Its adverse effects are infrequent and are presented in Table 2. We ought to mention that it seems to have fewer adverse behavioural effects compared to LEV.29 Its drawbacks is that it has exhibited more drug-drug interactions compared to LEV, as it can alter the function, and its function be altered by, other hepatic enzyme inducers.10

Cannabidiol (CBD)

Cannabidiol is a molecule obtained from the cannabis plant, but unlike tetrahydrocannabinol (THC) it does not interact with cannabinoid receptor B1, so it has antiepileptic effects but no psychoactive effects.30 Its mechanism of action is not fully understood, but it is hypothesised that it may involve an increase in GABA activity through the modulation of the GABA-A receptor, which in turn could regulate intracellular calcium flux through various receptors (TRPV, VDAC, GPR55), and that it may have a mild anti-inflammatory effect mediated by adenosine.10,31 Recently, the FDA (2018) and the EMA (2019) have added the indication of management of seizures in patients aged 2 or more years with Dravet syndrome or Lennox-Gastaut syndrome. The efficacy of CBD was proven in 3 double-blind randomised controlled trials conducted in the paediatric and adult populations,30,32,33 although there is also evidence from other studies suggesting that it may be effective in other forms of epilepsy and epileptic syndromes.34,35 Its main advantage is that it has proven effective in 2 of the epileptic syndromes that are most difficult to control. Its main drawbacks are that it frequently produces adverse events (Table 2), that it interacts with several other antiepileptic drugs and that it may cause hepatotoxicity, especially when used in combination with VPA or VPA and CLB, which requires close monitoring of laboratory parameters (Table 3).

Table 3.

Main advantages and disadvantages of third-generation antiepileptic drugs in the paediatric population.

Main advantages  Drug  Main disadvantages 
Predictable linear kineticsLong half life (20–24h)Single daily dosePredictable adverse eventsBetter tolerated than CBZWithout the inductor effect of CBZWell-defined dose in children  Eslicarbazepine (ESL)  Cytochrome CYP2C19 inhibitor (interaction with PHT)Class I neurologic adverse events (somnolence)HyponatremiaHigher frequency of adverse events if used in combination with other drugs acting on sodium channelsLimited experience in children 
Rapid onsetPredictable linear kineticsLow binding of plasma proteinsDoes not induce enzymesHepatic metabolism not involving CYP450 pathwayRenal eliminationNo significant drug–drug interactionsPossible parenteral administrationBroad range of formulationsSynergistic effect with other antiepileptic drugs (LEV, VPA,...)  Lacosamide (LCM)  Currently limited to focal-onset epilepsyClass I neurologic adverse events that are dose-dependent and are worse in combined treatment with other drugs that block voltage-gated sodium channels 
Withdrawn from the market  Retigabine (RTG)  Adverse events including dermatological changes in pigmentation (retinal degeneration). 
Predictable linear kineticsLong half-life (105h)Hepatic metabolism not involving CYP450 pathwayPotentially wide spectrum (other forms of epilepsy)Administration in a single daily dose (at night)Well defined and predictable adverse effectsBroad range of formulationsFew cognitive effectsDoes not cause sleep disturbances  Perampanel (PER)  High rate of protein-binding interactionsAffected by other enzyme inductorsInteracts with other antiepileptic drugs (OXC, TPM)Class I neurologic adverse eventsPossible development of severe behavioural disordersLack of oral suspension or intravenous solutionNo established paediatric dose per kg of body weight per day. 
Treatment option in patients with very difficult to control epilepsy (drug-resistant epilepsy associated with tuberous sclerosis)Effective against other diseases associated with tuberous sclerosis (SEGA, renal angiomyolipoma)  Everolimus (EVR)  Indication currently limited to drug-resistant epilepsy in patients with tuberous sclerosisFrequent adverse events (stomatitis, infections etc.)Dosing requires monitoring of drug levels (frequent blood tests) 
Broad spectrumRapid onsetPossible rapid titrationPredictable linear kineticsLow binding of plasma proteinsNo drug-drug interactionsAdequate balance between efficacy and tolerability. Better tolerated than LEVBroad range of formulations, including oral suspension. It can be administered by enteral or parenteral routes.  Brivaracetam (BRV)  Type I neurologic adverse events (somnolence, irritability)Scarce data overall for non-focal seizuresLittle experience in the paediatric population 
Treatment option in patients with difficult to control epilepsy (drug-resistant epilepsy associated with Dravet syndrome or Lennox-Gastaut syndrome), with a sustained positive effectPotentially wide spectrum (other forms of drug-resistant epilepsy), with a sustained positive effectAbsence of psychotropic effects  Cannabidiol (CBD)  Class I neurologic adverse effects, dose-dependent (somnolence, sedation, ataxia, behavioural changes)Increases plasma levels of CLB (>166%) which requires a reduction in the dose of CLBPotential hepatotoxicity in combination with VPA 
Final comments

In this article, we attempted to summarise the main characteristics of the new AEDs used in paediatrics. Most of these third-generation drugs are effective, safe and generally well tolerated in children. If we focused on those intended for broader use (BRV, ESL, LCM, PER), while their effectiveness has been inferred by the extrapolation of data from studies in the adult population, it will be the day-to-day clinical experience that will reveal the true potential of these drugs, probably leading to expanding their spectrum and defining new indications or synergistic effects with other treatments (as has been the case of most antiepileptic drugs in the past). A recently published, large meta-analysis (it analysed 19 double-blind randomised controlled trials, with n=7245) on the use of third-generation anticonvulsants (ESL, LCM, PER, BRV) in adults with focal epilepsy did not find significant differences in effectiveness, although the data suggested that BRV was better tolerated compared to the other drugs, independently of the dose used.36 Thus, taking into account that all of these drugs seem to be equally effective and safe, the management of epilepsy is becoming increasingly individualised, with selection of one drug or another based on tolerance, synergistic effects, interactions or contraindications, although the goal of treatment remains the same for all: to improve the quality of life of children with epilepsy and their families.

References
[1]
A.K. Nguki, I. Bottomley, I. Kleinschmidt, J.W. Sander, C.R. Newton.
Estimation of the burden of active and life-time epilepsy: a meta-analytic approach.
[2]
K. Saad.
Childhood epilepsy: an update on diagnosis and management.
Am J Neurosc, 5 (2014), pp. 36-51
[3]
R. Guerrini.
Epilepsy in children.
[4]
H. Kaur, B. Kumar, B. Medhi.
Antiepileptic drugs in development pipeline: a recent update.
Eneurolog Sci, 4 (2016), pp. 42-51
[5]
J.H. Cross, G. Kluger, L. Lagae.
Advancing the management of childhood epilepsies.
Eur J Pediatr Neurol, 17 (2013), pp. 334-347
[6]
S. Shinnar, J.M. Pellock.
Update on the epidemiology and prognosis of pediatric epilepsy.
J Child Neurol, 17 (2002), pp. s4-s17
[7]
W.A. Hauser, P.N. Banerjee.
Epidemiology of epilepsy in children.
Pediatric epilepsy diagnosis and treatment, 3rd ed., pp. 147-164
[8]
H.S. White, M.D. Smith, K.S. Wilcox.
Mechanisms of action of antiepileptic drugs.
Int Rev Neurobiol, 81 (2007), pp. 85-110
[9]
P. Kwan, G.J. Sills, M.J. Brodie.
The mechainsms of action of commonly used antiepileptic drugs.
Pharmacol Therapeut, 90 (2001), pp. 21-34
[10]
B.W. Abbou-Khalil.
Update on antiepileptic drugs 2019.
Continuum (Minneap Minn), 25 (2019), pp. 508-536
[11]
R. Moavero, L. Rosa Pisani, F. Pisani, P. Curatolo.
Safety and tolerability profile of new antiepileptic drug treatment in children with epilepsy.
Expert Opin Drug Saf, 17 (2018), pp. 1015-1028
[12]
X. Liu, P.R. Carney, R. Bussing, R. Segal, L.B. Cottler, A.G. Winterstein.
Trends in antiepileptic drug use in children and adolescents with epilepsy.
Pediatr Neurol, 74 (2017), pp. 32-40
[13]
A. Arzimanoglou, O. D‘Cruz, D. Nodli, S. Shinnar, G.I. Holmes.
for PEACE. A review of the new antiepileptic drugs for focal-onset seizures in pediatrics: role of extrapolation.
Pediatr Drugs, 20 (2018), pp. 249-264
[14]
International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Harmonised Guideline. Addendum to ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population. 2016. Available from www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/E11R1EWG_Step4_Addendum_2017_0818.pdf [accessed 01.09.19]
[15]
European Medical Agency. Reflection paper on extrapolation of efficacy and safety in paediatric medicine development—draft. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_.procedural_guideline/2016/04/WC500204187.pdf [accessed 01.09.19].
[16]
M. Bialer, P. Soares-da-Silva.
Pharmacokinetics and drug interactions of eslicarbazepine acetate.
[17]
S. Józwiak, P. Veggiotti, J. Moreira, H. Gama, F. Rocha, P. Soares-da-Silva.
Effects of adjuntive eslicarbazepine acetate on neurocognitive functioning in children with refractory focal-onset seizures.
Epilepsy Behav, 81 (2018), pp. 1-11
[18]
M.A. Rogawski, A. Tofighy, H.S. White, A. Matagne, C. Wolff.
Current understanding of the mechanism of action of the antiepileptic drug lacosamide.
Epilepsy Res, 11 (2015), pp. 189-205
[19]
J.S. Ortiz de la Rosa, L.D. Ladino, L.D. Rodríguez, M.C. Rueda, J.P. Polanía, A.C. Castañeda.
Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: a systematic review.
[20]
W. Rosenfeld, N.B. Fountain, G. Kaybrys.
Safety and efficacy of adjunctive lacosamide among patients with partial onset seizures in a long-term open-label extension trial up to 8 years.
Epilespy Behav, 41 (2014), pp. 164-170
[21]
D.J. Walleigh, A. Legido, I. Valencia.
Ring chromosome 20: a pediatric potassium channelopathy responsive to treatment with ezogabine.
Pediatr Neurol, 49 (2013), pp. 368-369
[22]
P. De Liso, P. Moavero, G. Coppola, P. Curatolo, R. Cusmai, G. de Sarro, et al.
Current role of perampanel in pediatric epilepsy.
Ital J Pediatr, 43 (2017), pp. 51
[23]
L. Kuang-lin, L. Jainn-Jim, C. Ming-Liang, H. Po-Cheng, H. Meng-Ying, C.et al. I-Jun.
Efficacy and tolerability of perampanel in children and adolescents with pharmacoresistant epilepsy: the first real-world evaluation in Asian pediatric neurology clinics.
Epilep Behav, 85 (2018), pp. 188-194
[24]
C.J. Chu-Shore, P. Major, S. Composano, D. Muzykewicz, E.A. Thiele.
The natural history of epilepsy in tuberous sclerosis complex.
Epilepsia, 51 (2010), pp. 1236-1241
[25]
D.A. Krueger, M.M. Care, K. Holland, K. Agricola, C. Tudor, P. Mangeshkar, et al.
Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.
N Engl J Med, 363 (2010), pp. 1801-1811
[26]
D.A. Krueger, K. Wilfong, K. Holland-Bouley, A.E. Anderson, K. Agricola, C. Tudor, et al.
Everolimus treatment of refractory epilepsy in tuberous sclerosis complex.
Ann Neurol, 74 (2013), pp. 679-687
[27]
J.A. French, J.A. Lawson, Z. Yapici, H. Ikeda, T. Polster, R. Nabbout, et al.
Adjuntive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomized, double-blind, placebo-controlled study.
Lancet, 388 (2016), pp. 2153-2163
[28]
L.J. Stephen, J.M. Brodie.
Brivaracetam: a novel antiepileptic drug for focal-onset seizures.
Ther Adv Neruol Disord, 11 (2017),
[29]
E. Liu, D. Dilley, B. McDonough, A. Stockis, T. Daniels.
Safety and tolerability of adjunctive brivaracetam in pediatric patients < 16 years with epilepsy: an open-label trial.
Pediatr Drugs, 21 (2019), pp. 291-301
[30]
O. Devinsky, H. Cross, L. Laux, E. Marsh, I. Miller, R.et al. Nabbout.
Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.
N Engl J Med, 376 (2017), pp. 2011-2020
[31]
C. Ibeas Bith, T. Chen, A.V.W. Nunn, M. Bazelot, M. Dallas, J. Whalley.
Molecular targets of cannabidiol in neurological disorders.
Neurotherapeutics, 12 (2015), pp. 699-730
[32]
O. Devinsky, A.D. Patel, J.H. Cross, V. Villanueva, E.C. Wirrell, M. Privitera, et al.
Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome.
New Engl J Med, 378 (2018), pp. 1888-1897
[33]
E.A. Thiele, E.D. Marsh, J.A. French, M. Mazurkiewithz-Beldzinska, S.R. Benbadis, C. Joshi, et al.
Cannabidiol in patienst with seizures associated with lennox Gastaut syndrome (GWPCARE4): a randomized, double-bling, placebo-controlled phase 3 trial.
Lancet, 391 (2018), pp. 1085-1096
[34]
O. Devinsky, E. Marsh, D. Friedman, E. Thiele, L. Laux, J. Sullivan, et al.
Canabidiol in patients with treatment-resistant epilepsy; an open-label intervetional trial.
Lancet Neurol, 15 (2016), pp. 270-278
[35]
M. Scott Perry.
Don’t fear the refeer – evidence mounts for plant-based cannabidiol as treatment for epilepsy.
Epilepsy Curr, 19 (2019), pp. 93-95
[36]
Z. Li-Na, C. Deng, W. Hai-jiao, X. Da, T. Ge, L. Ling.
Indirect comparison of third-generation antiepileptic drugs as adjunctive treatment for uncontrolled focal epilepsy.
Epilepsy Res, 139 (2018), pp. 60-72

Please cite this article as: Málaga I, Sánchez-Carpintero R, Roldán S, Ramos-Lizana J, García-Peñas JJ. Nuevos fármacos antiepilépticos en Pediatría. An Pediatr (Barc). 2019;91:415.

Copyright © 2019. Asociación Española de Pediatría
Idiomas
Anales de Pediatría (English Edition)

Subscribe to our newsletter

Article options
Tools
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.