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Špilárová Z, Sládková S, Bělohlávková A, Česká K, Hanáková P, Horák O, Jahodová A, Knedlíková L, Kolář S, Ebel M, Kudr M, Ošlejšková H, Ryzí M, Španělová K, Štěrbová K, Koubová A, Kršek P, Danhofer P. Brivaracetam use in children with epilepsy: A retrospective multicenter study. Seizure 2024; 121:243-252. [PMID: 39303432 DOI: 10.1016/j.seizure.2024.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 09/22/2024] Open
Abstract
PURPOSE This retrospective multicenter study aimed to assess the efficacy and safety of brivaracetam (BRV) in pediatric epilepsy. METHODS Our cohort consisted of 93 children (mean age 11.5 ± 7.5 years) with a wide spectrum of pediatric epilepsy, including epileptic encephalopathy and generalized epilepsy. Of these, 61 (60.4%) were diagnosed with focal epilepsy, 19 (15.8%) with generalized epilepsy, and 16 (15.8%) with combined epilepsy, while 8 patients (7.9%) had an unknown epilepsy type. The cohort included rare epilepsy syndromes: 8 patients with Lennox-Gastaut syndrome, 3 with Dravet syndrome, and 1 with Rasmussen syndrome. Patients had a history of various antiseizure medications (ASMs) (6.42 ± 3.15), and on average, were being treated with more than two (2.57 ± 1.16) drugs at the time of BRV deployment. RESULTS Retention rates were high, with 80.6% of patients adhering to treatment at 3 months, 66.7% at 6 months, and 45.2% at 12 months. In 29 patients (30.1%), BRV was added in an overnight switch from levetiracetam (LEV), resulting in a reduction of behavioral adverse effects (AEs) in 5 patients (17.2%). The response rate was 25.8% at 3 months, 16.1% at 6 months, and 17.2% at 12 months, with no responders in the epileptic encephalopathy group. Therapy tolerance was notable, with 70 patients (75.3%) reporting no AEs. Transient AEs occurred in 10 patients (10.7%), and in 13 cases (14.0%), the AEs warranted dose adjustment or discontinuation of BRV. CONCLUSION Approximately one-fifth of pediatric patients with drug-resistant epilepsy responded to BRV, with the best response observed in patients with focal seizures. However, the impact on patients with epileptic encephalopathy was limited.
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Affiliation(s)
- Z Špilárová
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - S Sládková
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - A Bělohlávková
- Department of Pediatric Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Motol Epilepsy Center, Full Member of ERN EpiCARE, Prague, Czech Republic
| | - K Česká
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - P Hanáková
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - O Horák
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - A Jahodová
- Department of Pediatric Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Motol Epilepsy Center, Full Member of ERN EpiCARE, Prague, Czech Republic
| | - L Knedlíková
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - S Kolář
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - M Ebel
- Department of Pediatric Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Motol Epilepsy Center, Full Member of ERN EpiCARE, Prague, Czech Republic
| | - M Kudr
- Department of Pediatric Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Motol Epilepsy Center, Full Member of ERN EpiCARE, Prague, Czech Republic
| | - H Ošlejšková
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - M Ryzí
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - K Španělová
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic
| | - K Štěrbová
- Department of Pediatric Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Motol Epilepsy Center, Full Member of ERN EpiCARE, Prague, Czech Republic
| | - A Koubová
- Faculty of Pharmacy, Masaryk University, Brno, Czech Republic
| | - P Kršek
- Department of Pediatric Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Motol Epilepsy Center, Full Member of ERN EpiCARE, Prague, Czech Republic
| | - P Danhofer
- Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Center, Full Member of ERN EpiCARE, Czech Republic.
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Ettienne EB, Russo E, Striano P, Grant-Kels JM, Rose K. Did pediatric drug development advance epilepsy treatment in young patients? It is time for new research goals. World J Methodol 2024; 14:92371. [PMID: 38983658 PMCID: PMC11229878 DOI: 10.5662/wjm.v14.i2.92371] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/13/2024] [Accepted: 04/16/2024] [Indexed: 06/13/2024] Open
Abstract
Modern drugs have changed epilepsy, which affects people of all ages. However, for young people with epilepsy, the framework of drug development has stalled. In the wake of the thalidomide catastrophe, the misconception emerged that for people < 18 years of age drugs, including antiseizure medications (ASMs), need separate proof of efficacy and safety, overall called "pediatric drug development". For ASMs, this has changed to some degree. Authorities now accept that ASMs are effective in < 18 years as well, but they still require "extrapolation of efficacy," as if minors were another species. As a result, some of the pediatric clinical epilepsy research over the past decades was unnecessary. Even more importantly, this has hampered research on meaningful research goals. We do not need to confirm that ASMs work before as they do after the 18th birthday. Instead, we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs' uses. Herein we discuss how to proceed in this endeavor.
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Affiliation(s)
- Earl B Ettienne
- College of Pharmacy, Howard University College of Pharmacy, Washington, DC 20059, United States
| | - Emilio Russo
- Department of Health Sciences, School of Medicine, Russo, University "Magna Graecia" of Catanzaro, Catanzaro 88100, Italy
| | | | - Jane M Grant-Kels
- Department of Dermatology, University of Connecticut Health Center, Farmington, CT 06032, United States
| | - Klaus Rose
- klausrose Consulting, Pediatric Drug Development and more, Medical Science, CH-4125 Riehen, Switzerland
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Schoemaker R, Krauwinkel W, Elshoff JP, Stockis A. Brivaracetam exposure-response predictions in pediatric patients from age 1 month: Extrapolation of levetiracetam adult-pediatric scaling to brivaracetam. Epilepsy Res 2024; 202:107332. [PMID: 38518434 DOI: 10.1016/j.eplepsyres.2024.107332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 01/25/2024] [Accepted: 02/19/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for the antiseizure medication (ASM) brivaracetam (BRV) was previously extended to children aged 4-16 years by using a pediatric BRV population PK model. Effects were scaled using information from a combined adult-pediatric PK/PD model of a related ASM, levetiracetam (LEV). OBJECTIVE To scale an existing adult population PK/PD model for BRV to children aged 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, and to predict the effective dose of BRV in children aged 1 month to < 4 years using the adult BRV PK/PD model modified for the basal seizure rate in children. MATERIAL AND METHODS An existing adult population PK/PD model for BRV was scaled to children aged from 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, an ASM binding to the same target protein as BRV. An existing adult-pediatric PK/PD model for LEV was extended using data from UCB study N01009 (NCT00175890) to include children as young as 1 month of age. The BRV population PK model was updated with data up to 180 days after first administration from BRV pediatric studies N01263 (NCT00422422) and N01266 (NCT01364597). PK and PD simulations for BRV were performed for a range of mg/kg doses to predict BRV effect in pediatric participants, and to provide dosing recommendations. RESULTS The extended adult-pediatric LEV PK/PD model was able to describe the adult and pediatric data using the same PD model parameters in adults and children and supported the extension of the adult BRV PK/PD model to pediatric patients aged 1 month to < 4 years. Simulations predicted exposures similar to adults receiving BRV 100 mg twice daily (b.i.d.), when using 3 mg/kg b.i.d. for weight < 10 kg, 2.5 mg/kg b.i.d. for weight ≥ 10 kg and < 20 kg, and 2 mg/kg b.i.d. for weight ≥ 20 kg in children aged 1 month to < 4 years. PK/PD simulations show that maximum BRV response is expected to occur with 2-3 mg/kg b.i.d. dosing of BRV in children aged 1 month to < 4 years, with an effective dose of 1 mg/kg b.i.d. for some participants. CONCLUSION Development of an adult-pediatric BRV PK/PD model allowed characterization of the exposure-response relationship of BRV in children aged 1 to < 4 years, providing a maximal dose allowance based on weight.
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Affiliation(s)
- Rik Schoemaker
- Occams, Malandolaan 10, 1187 HE Amstelveen, the Netherlands
| | | | - Jan-Peer Elshoff
- UCB Pharma, Alfred-Nobel-Strasse 10, 40789 Monheim am Rhein, Germany
| | - Armel Stockis
- UCB Pharma, Chemin du Foriest, B1420 Braine-l'Alleud, Belgium
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Toptan HH, Karadag NN, Topcuoglu S, Ozalkaya E, Dincer E, Cakir H, Gunes AO, Karatekin G. Comparative Outcomes of Levetiracetam and Phenobarbital Usage in the Treatment of Neonatal Seizures: A Retrospective Analysis. Healthcare (Basel) 2024; 12:800. [PMID: 38610222 PMCID: PMC11011900 DOI: 10.3390/healthcare12070800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/14/2024] Open
Abstract
OBJECTIVES AND AIM The primary aim of this study was to conduct a comparative analysis of the safety and efficacy of levetiracetam (LEV) and phenobarbital (PB) as first-line treatments for neonatal seizure management. This study was designed to measure and compare the incidence of adverse effects and to determine the discharge and mortality rates associated with the use of these antiseizure medications (ASMs). Through this comparison, this research sought to provide insights to optimise care for neonates experiencing seizures. MATERIALS AND METHODS This retrospective cohort study evaluated 104 neonates treated for seizures at Zeynep Kamil Hospital from 2015 to 2020 after excluding those on non-PB/LEV antiseizure medications. Seizures were characterised using electroencephalogram (EEG) and categorised according to aetiology and frequency. Treatment efficacy was gauged by seizure cessation, as confirmed using EEG. Adverse effects and demographic data were recorded. Statistical analyses were conducted using SPSS, employing the Shapiro-Wilk, independent t-test, Mann-Whitney U test, and chi-square test, with a significance threshold of p < 0.05. RESULTS Overall, 104 neonates treated with first-line ASM were evaluated for efficacy; PB was administered in 68.26% of the cases, while LEV was utilised in 31.74%. The total complete response rate was 40.38%, with no significant difference between the PB and LEV groups (p = 0.309). The incidence rate ratios (IRRs) demonstrated that seizure frequency profoundly influenced treatment effectiveness, with IRRs of 2.09 for rare seizures, 3.25 for frequent seizures, and 4.01 for status epilepticus, indicating a higher treatment response rate with increasing seizure frequency. For second-line treatment, among a subset of 62 patients, PB had a slight, non-significant advantage over LEV, with an odds ratio of 1.09, suggesting a marginally better response to LEV. Adverse events were significantly more frequent in the PB group, affecting 19 of 67 neonates (28.36%), compared to only 2 of 71 neonates (2.82%) in the LEV group (p < 0.001). No significant difference was observed in the discharge rates between the two groups (PB, 67.61%; LEV, 75.76%; p = 0.674). Interestingly, the mortality rate was significantly higher in the LEV group (45.45%) than that in the PB group (22.54%; p = 0.045). CONCLUSION This study underscores LEV's superior safety profile over PB in neonatal seizure management, evidenced by a significantly lower rate of adverse events. PB seems to be more effective in the second-line treatment of neonatal seizures. Despite the lack of significant differences in the discharge rates, the higher mortality rate associated with LEV warrants further investigation. These findings advocate the cautious selection of antiepileptic drugs in neonatal care, with a preference for LEV based on its safety profile.
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Affiliation(s)
- Handan Hakyemez Toptan
- Department of Neonatology, University of Health Sciences, Zeynep Kamil Maternity and Children’s Disease Health Training and Research Center-Istanbul, 34668 Istanbul, Turkey; (N.N.K.); (S.T.); (E.O.); (A.O.G.)
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Håkansson S, Wickström R, Zelano J. Selection and Continuation of Antiseizure Medication in Children With Epilepsy in Sweden From 2007 to 2020. Pediatr Neurol 2023; 144:19-25. [PMID: 37116405 DOI: 10.1016/j.pediatrneurol.2023.03.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 02/03/2023] [Accepted: 03/23/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND Knowledge on antiseizure medication (ASM) use and retention for children with epilepsy is limited, partly because of extensive off-label use of newer drugs with limited registration. We used prescription data to study prescription patterns on a population-wide scale and compared the proportion of patients remaining on monotherapy of ASMs with and without formal indication for different age groups. METHODS A total of 14,681 individuals aged <18 years were included, using cross-referenced Swedish registers from 2007 to 2020. Kaplan-Meier retention rates were calculated for all ASMs. The most common pathways of the first three medications per patient were analyzed. RESULTS In children older than one month and up to age one year, monotherapy retention rates were the highest for oxcarbazepine, valproic acid, and carbamazepine. Among children aged one to five years, oxcarbazepine and levetiracetam were among ASMs that do not have a monotherapy indication in Sweden but still had high retention rates. In the age group five to 12 years, lamotrigine and oxcarbazepine had the highest retention rate. In males aged 12 to 18 years, valproic acid was the most common choice followed by lamotrigine, whereas lamotrigine was the first choice of ASM for females, exceeding the second and third most common options levetiracetam and oxcarbazepine by a factor of two and three, respectively. CONCLUSION Off-label medication is common in children with epilepsy but does not seem to be associated with lower retention. The restrictions regarding valproic acid for females of childbearing age seem to have been well implemented in Swedish neuropediatric care.
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Affiliation(s)
- Samuel Håkansson
- Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Wallenberg Center for Molecular and Translational Medicine, Gothenburg University, Gothenburg, Sweden
| | - Ronny Wickström
- Neuropediatric Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Johan Zelano
- Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Wallenberg Center for Molecular and Translational Medicine, Gothenburg University, Gothenburg, Sweden.
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Zhang L, Li Y, Wang W, Wang C. Comparative antiseizure medications of adjunctive treatment for children with drug-resistant focal-onset seizures: A systematic review and network meta-analysis. Front Pharmacol 2022; 13:978876. [PMID: 36588743 PMCID: PMC9800847 DOI: 10.3389/fphar.2022.978876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Purpose: In this study, we intended to compare and rank the efficacy and acceptability of antiseizure medications (ASMs) for adjunctive treatment of children with drug-resistant focal-onset seizures. Method: We conducted a computerized search of PubMed, EMBASE, Cochrane Library, Web of Science, and Google Scholar to identify eligible randomized controlled trials (RCTs) published before 31 May 2022. We included studies evaluating the efficacy and tolerability of antiseizure medications for children with drug-resistant focal-onset seizures. The efficacy and safety were reported in terms of responder and dropout rate along with serious adverse events, the outcomes were ranked with the surface under the cumulative ranking curve (SUCRA). Results: A total of 14 studies (16 trials) with 2,464 patients were included, involving 10 active antiseizure medications. For the primary endpoint of at least 50% reduction in focal-onset seizures, the surface under the cumulative ranking curve ranking suggested that lamotrigine and levetiracetam were more effective as compared with other antiseizure medications; moreover, levetiracetam had the highest probability of rank first for achieving seizure freedom. Concerning tolerability, oxcarbazepine and eslicarbazepine acetate were associated with higher dropout rates relative to other antiseizure medications and placebo, and topiramate was associated with higher occurrence of side effects. No significant differences were found between active antiseizure medications concerning dropout for side effects. Conclusion: According to the surface under the cumulative ranking curve ranking, lamotrigine, levetiracetam, and oxcarbazepine were more efficacious than other active antiseizure medications in terms of responder rate. Concerning tolerability, oxcarbazepine was more likely to lead to dropout and topiramate was associated with higher occurrence of side effects.
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ALSaeedy M, Hasan A, Al-Adhreai A, Alrabie A, Qaba H, Mashrah A, Öncü-Kaya EM. An overview of liquid chromatographic methods for analyzing new generation anti-epileptic drugs. J LIQ CHROMATOGR R T 2022. [DOI: 10.1080/10826076.2022.2134146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Mohammed ALSaeedy
- Department of Chemistry, Faculty of Applied Sciences, Dhamar University, Dhamar, Yemen
- Department of Chemistry, Faculty of Sciences, Eskisehir Technical University, Eskisehir, Turkey
- Department of Chemistry, Faculty of Education-Albaydha, Albaydha University, Albaydha, Yemen
| | - Ahmed Hasan
- Department of Pharmacology, Graduation School of Health Science, Anadolu University, Eskisehir, Turkey
| | - Arwa Al-Adhreai
- Department of Chemistry, Faculty of Applied Sciences, Dhamar University, Dhamar, Yemen
- Department of Chemistry, Maulana Azad of Arts, Science and Commerce, Aurangabad, India
| | - Ali Alrabie
- Department of Chemistry, Faculty of Education-Albaydha, Albaydha University, Albaydha, Yemen
- Department of Chemistry, Maulana Azad of Arts, Science and Commerce, Aurangabad, India
| | - Hafsah Qaba
- Department of Analytical Chemistry, Graduation School of Health Sciences, Anadolu University, Eskisehir, Turkey
| | - Abdulrahman Mashrah
- Department of Food Science and Technology, Faculty of Agriculture and Food Sciences, Ibb University, Ibb, Yemen
- Department of Food Engineering, Institute of Natural Sciences-Sakarya, Sakarya University, Sakarya, Turkey
| | - Elif Mine Öncü-Kaya
- Department of Chemistry, Faculty of Sciences, Eskisehir Technical University, Eskisehir, Turkey
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French JA, Cleary E, Dlugos D, Farfel G, Farrell K, Gidal B, Grzeskowiak CL, Gurrell R, Harden C, Stalvey TJ, Tsai J, Wirrell EC, Blum D, Fountain N. Considerations for determining the efficacy of new antiseizure medications in children age 1 month to younger than 2 years. Epilepsia 2022; 63:2664-2670. [PMID: 35835554 PMCID: PMC9804346 DOI: 10.1111/epi.17366] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/12/2022] [Accepted: 07/12/2022] [Indexed: 01/05/2023]
Abstract
OBJECTIVES Drug treatment for children with epilepsy should, ideally, be governed by evidence from adequate and well-controlled clinical studies. However, these studies are difficult to conduct, and so direct evidence supporting the informed use of specific drugs is often lacking. The Research Roundtable for Epilepsy (RRE) met in 2020 to align on an approach to therapy development for focal seizures in children age 1 month <2 years of age. METHODS The RRE reviewed the regulatory landscape, epidemiology, seizure semiology, antiseizure medicine pharmacology, and safety issues applicable to this population. RESULTS After reviewing evidence, the conclusion was that pediatric efficacy trials would be impracticable to conduct but a waiver of the regulatory requirement to conduct any study would lead to an absence of information to guide dosing in a critical population. Review of available data and discussion of RRE attendees led to the conclusion that the requirements for extrapolation of efficacy from older children down to infants from age 1 month to <2 years old appeared to be met. After the RRE, the US Food and Drug Administration (FDA) approved brivaracetam for use in children with focal epilepsy above the age of 1 month in August 2021 and lacosamide in October 2021, both based on the principle of extrapolation from data in older children. SIGNIFICANCE These recommendations should result in more rapid accessibility of antiseizure medications for infants.
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Affiliation(s)
| | | | - Dennis Dlugos
- Departments of Neurology and PediatricsChildren's Hospital of Philadelphia, PerelmanPhiladelphiaPennsylvaniaUSA
| | - Gail Farfel
- Zogenix, a UCB CompanyEmeryvilleCaliforniaUSA
| | - Kathleen Farrell
- Research and New Therapies ProgramEpilepsy Foundation of AmericaMarylandUSA
| | - Barry Gidal
- University of Wisconsin School of PharmacyMadisonWisconsinUSA
| | | | | | - Cynthia Harden
- Clinical Development DivisionXenon Pharmaceuticals Inc.BurnabyBritish ColumbiaCanada
| | | | | | - Elaine C. Wirrell
- Divisions of Child and Adolescent Neurology and Epilepsy, Department of NeurologyMayo ClinicRochesterMinnesotaUSA
| | | | - Nathan Fountain
- Department of NeurologyUniversity of VirginiaCharlottesvilleVirginiaUSA
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Yang C, Yang Y, Peng Y, Zhang L, Yu D. Efficacy and safety of lacosamide in pediatric patients with epilepsy: A systematic review and meta-analysis. Epilepsy Behav 2022; 134:108781. [PMID: 35914435 DOI: 10.1016/j.yebeh.2022.108781] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/16/2022] [Accepted: 05/30/2022] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Lacosamide (LCM), is a third-generation antiseizure medicine, with limited clinical evidence for use in pediatric populations. We aimed to evaluate evidence for the efficacy and safety of LCM in pediatric patients with epilepsy. METHODS A systematic review was performed using literature published from inception to February 2022 identified in MEDLINE, Embase, Cochrane Library, and four Chinese databases. Efficacy and safety outcome data were collected, and a meta-analysis was performed. RESULT Twenty-one studies involving 1230 pediatric patients were included. The median percent reduction in seizure frequency per 28 days from baseline to maintenance was 33.1% (95% confidence interval [CI] 22.7%, 43.5%). After 6 months of treatment, the 50%, 75%, and 100% responder rates were 53.3% (95% CI 40.7%, 65.9%), 28.3% (95% CI 20.8%, 35.8%), and 20.4% (95% CI 12.6%, 28.2%), respectively. After 12 months of treatment, the 50%, 75%, and 100% responder rates were 42.0% (95% CI 29.5%, 54.5%), 19.5% (95% CI 11.1%, 27.8%), and 15.2% (95% CI 6.6%, 23.8%), respectively. The most common adverse events (AEs) were drowsiness (15.0%), dizziness (9.9%), and somnolence (8.3%). CONCLUSION Lacosamide is generally effective and well tolerated to use in children with epilepsy. However, further research with high-quality data and long-term follow-up of LCM use in pediatric populations is needed.
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Affiliation(s)
- Chunsong Yang
- Department of Pharmacy, Evidence-based Pharmacy Center, West China Second Hospital, Sichuan University, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, China
| | - Yang Yang
- Department of Trauma Center Ward 2, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, China
| | - Yuxuan Peng
- Department of Trauma Center Ward 2, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, China
| | - Lingli Zhang
- Department of Pharmacy, Evidence-based Pharmacy Center, West China Second Hospital, Sichuan University, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, China.
| | - Dan Yu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, China; Department of Children's Genetic Endocrinology and Metabolism, China; West China School of Pharmacy, Sichuan University, China
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Yang H, Yu D. Young children with multidrug-resistant epilepsy and vagus nerve stimulation responding to perampanel: A case report. World J Clin Cases 2022; 10:3511-3517. [PMID: 35611206 PMCID: PMC9048547 DOI: 10.12998/wjcc.v10.i11.3511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/23/2021] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Perampanel (PER), a third-generation antiepileptic drug, is a selective and noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, and has been approved for the treatment of adults and adolescents with focal epilepsy. However, there are only a few studies about the efficacy and tolerability of PER in young children with multidrug-resistant epilepsy. In this case, we aimed to share our clinical experience in this group.
CASE SUMMARY A 4-year-old boy without perinatal asphyxia and familial history of epilepsy began to have ictal seizures from age 14 mo, with jerky movement of four limbs and head nodding. Abnormal multifocal discharge and background activity were recorded through electroencephalography, and no pathogenic mutation was found in the whole exome sequencing for the patient and his parents. He had received valproate, levetiracetam, topiramate, oxcarbazepine, clonazepam and lacosamide sequentially at different times, but he still had frequent seizures even after vagus nerve stimulation (VNS) implantation. He was diagnosed with idiopathic multidrug-resistant epilepsy. However, his seizure frequency was significantly reduced after PER administration in a dose-dependent manner, and better cognitive behavior was observed. In addition, the adverse reactions of anger and aggression also appeared.
CONCLUSION PER is effective as add-on therapy for young children with multidrug-resistant epilepsy who have previously undergone VNS implantation.
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Affiliation(s)
- Hua Yang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dan Yu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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11
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Günbey C, Bilginer B, Oğuz KK, Söylemezoğlu F, Ergün EL, Akalan N, Topçu M, Turanlı G, Yalnızoğlu D. Lesional resective epilepsy surgery in childhood: Comparison of two decades and long-term seizure outcome from a single center. Epilepsy Res 2022; 181:106882. [DOI: 10.1016/j.eplepsyres.2022.106882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/22/2022] [Accepted: 02/04/2022] [Indexed: 11/26/2022]
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12
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Rose K, Ettienne EB, Grant-Kels JM, Striano P, Neubauer D, Tanjinatus O. Neurology's vital role in preventing unnecessary and potentially harmful pediatric studies. Expert Rev Neurother 2022; 22:209-219. [PMID: 35213279 DOI: 10.1080/14737175.2022.2045953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Regulatory authorities recognize two human populations: adults and children defined as <18 years. For drug approval, they demand separate studies. But humans mature slowly during puberty. The 18th birthday is an administrative limit that does not correspond to a physiological change. Separate drug approval before/after the 18th birthday reflects the children-are-therapeutic-orphans concept that emerged after 1962. The Food and Drug Administration (FDA) has backed away from this concept for antiepileptic drugs, but sticks to it in other areas. In contrast, the European Medicines Agency (EMA) is continuously expanding its demand for "pediatric" studies. Parents hesitate increasingly to let their children participate in questionable studies. AREAS COVERED Neurologists challenge the children-are-therapeutic-orphans mantra. Young patients do not need separate proof of efficacy & safety, but appropriate dosing recommendations. Minors should be treated as human beings, instead of being abused in questionable studies. EXPERT OPINION Young patients with multiple sclerosis and other neurological diseases deserve studies with therapeutic intentions. "Pediatric" careers have emerged in academia, regulatory authorities, and pharmaceutical companies. Institutional Review Boards/ Ethics Committees should suspend questionable "pediatric" studies and reject newly submitted ones. The medical professions should distance themselves from questionable "pediatric" research that reflects massive conflicts of interest.
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Affiliation(s)
- Klaus Rose
- Klausrose Consulting, Riehen, Switzerland
| | | | - Jane M Grant-Kels
- Dermatology Department, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Pasquale Striano
- Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, "G. Gaslini" Institute, Genova, Italy
| | - David Neubauer
- Department of Child, Adolescent & Developmental Neurology, University Children's Hospital, Ljubljana, Slovenia
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13
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Aeby A, Ceulemans B, Lagae L. Treatment of Focal-Onset Seizures in Children: Should This Be More Etiology-Driven? Front Neurol 2022; 13:842276. [PMID: 35330806 PMCID: PMC8940242 DOI: 10.3389/fneur.2022.842276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/24/2022] [Indexed: 01/22/2023] Open
Abstract
To accelerate the process of licensing antiseizure medication (ASM) in children, extrapolation of efficacy data for focal-onset seizures from adults to children ≥2 or ≥4 years of age is now accepted. We summarized the efficacy evidence from randomized, controlled trials that was used to grant approval for the pediatric indication of focal-onset seizures for the different ASMs available in Europe. Data from high-quality randomized, controlled trials in young children are limited, especially on the use of ASMs in monotherapy. Licensure trials are typically focused on seizure type irrespective of etiology or epilepsy syndrome. We elaborate on the importance of etiology- or syndrome-driven research and treatment, illustrating this with examples of childhood epilepsy syndromes characterized by predominantly focal-onset seizures. Some of these syndromes respond well to standard ASMs used for focal-onset seizures, but others would benefit from a more etiology- or syndrome-driven approach. Advances in molecular genetics and neuroimaging have made it possible to reveal the underlying cause of a child's epilepsy and tailor research and treatment. More high-quality randomized, controlled trials based on etiology or syndrome type are needed, including those assessing effects on cognition and behavior. In addition, study designs such as "N-of-1 trials" could elucidate possible new treatment options in rare epilepsies. Broadening incentives currently in place to stimulate the development and marketing of drugs for rare diseases (applicable to some epilepsy syndromes) to more common pediatric epilepsy types and syndromes might be a means to enable high-quality trials, and ultimately allow more evidence-based treatment in children.
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Affiliation(s)
- Alec Aeby
- Pediatric Neurology, Queen Fabiola Children's University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Berten Ceulemans
- Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Lieven Lagae
- Reference Center for Refractory Epilepsy, Pediatric Neurology, Department of Development and Regeneration, University Hospitals Leuven, Leuven, Belgium
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14
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Lukka PB, Woods M, Chhim R, Phelps SJ, Wheless JW, Meibohm B. Use of Real-World Data and Pharmacometric Modeling in Support of Lacosamide Dosing in Pediatric Patients Under 4 Years of Age. J Clin Pharmacol 2021; 61:881-888. [PMID: 33599301 DOI: 10.1002/jcph.1840] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/15/2021] [Indexed: 12/20/2022]
Abstract
The antiepileptic drug lacosamide (LCM) is approved in the United States and the European Union as monotherapy as well as adjunctive therapy for the treatment of focal seizures in children ≥4 years of age and adults. Using real-world therapeutic drug monitoring data, we performed a pharmacometric analysis for 315 pediatric patients (>1 month to <18 years of age) who received lacosamide as both monotherapy and adjunctive therapy. Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling with a 1-compartment structural model with linear elimination, where clearance and volume of distribution were allometrically scaled for body weight, with no further need for age-associated maturation functions. A covariate analysis for age, sex, race, and coadministration of other antiepileptic drugs identified phenobarbital and felbamate to significantly increase lacosamide clearance (1.71- and 1.46-fold, respectively). Based on the developed population pharmacokinetic model, simulations were performed in virtual pediatric patients to explore age-associated dose requirements to match lacosamide exposure in patient groups of different age with the exposure achieved in children ≥4 year of age with the weight-based dosing recommendations provided by the US Food and Drug Administration. Based on this approach, our analysis suggested that children ≥3 years of age needed the same dose as recommended by the US Food and Drug Administration for children ≥4 years of age (12 mg/kg/d), while children 1 to 3 years of age may need 13 to 14 mg/kg/d and infants between 1 month and 1 year of age may need 15 to 18 mg/kg/d (based on their actual age) to match the exposure seen in children ≥4 years of age.
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Affiliation(s)
- Pradeep B Lukka
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Megan Woods
- Department of Pharmacy, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
| | - Rebecca Chhim
- Department of Pharmacy, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
| | - Stephanie J Phelps
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - James W Wheless
- Division of Pediatric Neurology, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Neuroscience Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
| | - Bernd Meibohm
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
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15
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Chen M, Jiang Y, Ma L, Zhou X, Wang N. Comparison of the Therapeutic Effects of Sodium Valproate and Levetiracetam on Pediatric Epilepsy and the Effects of Nerve Growth Factor and γ-Aminobutyric Acid. IRANIAN JOURNAL OF PUBLIC HEALTH 2021; 50:520-530. [PMID: 34178799 PMCID: PMC8214608 DOI: 10.18502/ijph.v50i3.5593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background: We aimed to investigate the therapeutic effect of sodium valproate combined with levetiracetam on pediatric epilepsy and the effects of nerve growth factor and γ-aminobutyric acid. Methods: Eighty-three epileptic children admitted to Xuzhou Municipal Hospital of Xuzhou Medical University (Xuzhou, China) from Jan 2018 to Nov 2019 were collected and divided into a control group (40 cases, treated with sodium valproate alone) and an observation group (43 cases, treated with sodium valproate combined with levetiracetam). The therapeutic effect and incidence of adverse reactions were observed. The levels of nerve growth factor (NGF), γ-aminobutyric acid (GABA) and serum neuron-specific enolase (NSE) of children were compared. Changes of cognitive function and the total effective rate were evaluated. Logistic regression analysis was used to analyze the risk factors affecting the therapeutic effect. Results: After treatment, NGF, GABA and NSE in the observation group were significantly improved compared with those before treatment. The cognitive function of the observation group was significantly improved after treatment when compared with the control group. The total effective rate in the observation group was higher than that in the control group. Adverse reactions in the observation group were less than those in the control group. Seizure type, NGF, GABA, NSE and treatment methods were independent risk factors affecting the therapeutic effect of pediatric epilepsy. Conclusion: The application of sodium valproate combined with levetiracetam in the treatment of pediatric epilepsy is helpful to improve the overall therapeutic effect, significantly improve the cognitive function of children, and improve the levels of NGF, GABA and NSE.
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Affiliation(s)
- Min Chen
- Department of Pediatrics, Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou 221116, China
| | - Yazhou Jiang
- Department of Pediatrics, Suqian People's Hospital, Suqian 223800, China
| | - Li Ma
- Department of Pediatrics, Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou 221116, China
| | - Xuedian Zhou
- Department of Pediatrics, Heping Women and Children's Hospital of Xuzhou, Xuzhou 221000, China
| | - Nuan Wang
- Department of Neurology, Affiliated Hospital of China University of Mining and Technology, Xuzhou City, 221116, China
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16
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Chan PLS, Marshall SF, McFadyen L, Liu J. Pregabalin Population Pharmacokinetic and Exposure-Response Analyses for Focal Onset Seizures in Children (4-16 years) and Adults, to Support Dose Recommendations in Children. Clin Pharmacol Ther 2020; 110:132-140. [PMID: 33280106 PMCID: PMC8359225 DOI: 10.1002/cpt.2132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/21/2020] [Indexed: 02/05/2023]
Abstract
Pregabalin is approved in multiple countries as adjunctive therapy for adult patients with focal onset seizures (FOS; previously termed partial onset seizures). This study used population pharmacokinetic (PK) and exposure–response (E‐R) analyses from pooled pregabalin concentration and efficacy data to compare pregabalin exposure and E‐R relationships in pediatric and adult patients with FOS, to support pediatric dosage recommendations. A one‐compartment disposition model was used, with first‐order absorption and body surface area‐normalized creatinine clearance on clearance. Individual pregabalin average steady‐state concentrations were predicted and used in an E‐R analysis of efficacy. The E‐R relationship of pregabalin was similar in pediatric (4–16 years) and adult patients with FOS after accounting for differences in baseline natural log‐transformed 28‐day seizure rate and placebo effect. Population PK simulations showed that children aged 4–16 years and weighing ≥ 30 kg required pregabalin 2.5–10 mg/kg/day to achieve similar pregabalin exposure at steady‐state to adult patients receiving the approved doses of 150–600 mg/day. For children 4–16 years weighing < 30 kg, a higher pregabalin dose of 3.5–14 mg/kg/day was required to achieve equivalent exposure at steady‐state. The results support the dosage guidance provided in the pregabalin prescribing label, whereby pediatric patients (4–16 years) weighing < 30 kg should receive a 40% higher pregabalin dose (per kg of body weight) than patients weighing ≥ 30 kg to achieve similar exposure. Our combined modeling approach may provide guidance for future extrapolation assessment from adult to pediatric patients.
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Affiliation(s)
| | | | | | - Jing Liu
- Pfizer, Groton, Connecticut, USA
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17
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Rose K, Neubauer D, Grant-Kels JM. Ethical Issues in Pediatric Regulatory Studies Involving Placebo Treatment. JOURNAL OF PEDIATRIC EPILEPSY 2020. [DOI: 10.1055/s-0040-1712147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AbstractSeparate pediatric studies for antiepileptic drugs (AEDs) emerged with general separate drug approval in children and were defined by the U.S. Food and Drug Administration (FDA) as <17 years and by the European Union (EU) as <18 years. These administrative age limits are necessary in pediatrics, but they correspond variably with the physiological maturity of young patients and are not helpful for therapeutic decisions or as study inclusion criteria. AEDs are often effective for partial onset seizures (POS) in 2 to 17-year-olds as well as in ≥18-year-olds, if dosed correctly. Separate pediatric AED studies assume no difference between the legal and the physiological meaning of the word “child.” While the FDA now accepts efficacy of AEDs in POS in children ≥2 years, the EU still requires separate “pediatric” studies. For retigabine it waived all pediatric studies after having required 20 such studies over several years. We feel the current regulation creates a situation where many studies in children are done unnecessarily; we question the ethics of such an approach, which in our view, is morally wrong. Critical publications contributed to the FDA's shift of opinion for AEDs in POS but did not address the blur of different meanings of the word “child.”
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Affiliation(s)
- Klaus Rose
- Klausrose Consulting, Riehen, Switzerland
| | - David Neubauer
- Department of Child, Adolescent and Developmental Neurology, University Childrens' Hospital, Ljubljana, Slovenia
| | - Jane M. Grant-Kels
- Department of Dermatology, UConn Health, Farmington, Connecticut, United States
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18
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Auvin S, Avbersek A, Bast T, Chiron C, Guerrini R, Kaminski RM, Lagae L, Muglia P, Cross JH. Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions. Drugs 2020; 79:1917-1935. [PMID: 31734883 DOI: 10.1007/s40265-019-01223-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes.
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Affiliation(s)
- Stéphane Auvin
- PROTECT, INSERM U1141, Université de Paris, Paris, France. .,Service de Neurologie Pédiatrique, AP-HP, Hôpital Universitaire Robert-Debré, 48, Boulevard Sérurier, 75935, Paris Cedex 19, France.
| | | | - Thomas Bast
- The Kork Epilepsy Center, Kehl-Kork, Germany.,Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - Catherine Chiron
- PROTECT, INSERM U1141, Université de Paris, Paris, France.,Service de Neurologie Pédiatrique, AP-HP, Hôpital Necker-Enfanst Malades, Paris, France
| | - Renzo Guerrini
- Neuroscience Department, Children's Hospital Anna Meyer-University of Florence, Florence, Italy
| | - Rafal M Kaminski
- UCB Pharma, Braine-l'Alleud, Belgium.,Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland
| | - Lieven Lagae
- Department Development and Regeneration, Section Paediatric Neurology, University Hospitals, University of Leuven, Leuven, Belgium
| | | | - J Helen Cross
- UCL NIHR BRC Great Ormond Street Institute of Child Health, London, UK
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19
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McGuire S, Silva G, Lal D, Khurana DS, Legido A, Hasbani D, Carvalho KS, Melvin J, Valencia I. Safety and Efficacy of Brivaracetam in Pediatric Refractory Epilepsy: A Single-Center Clinical Experience. J Child Neurol 2020; 35:102-105. [PMID: 31617449 DOI: 10.1177/0883073819879276] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Brivaracetam is a new antiepileptic drug with limited data in children. The objective of this study was to assess the efficacy/tolerability of brivaracetam. This is a retrospective chart review of children/adolescents with refractory epilepsy treated with brivaracetam from 2016 to 2018. The primary outcome was seizure reduction (decrease in seizure frequency >50%). Twenty-three patients were identified. Mean age at initiation was 12.5 years. Fourteen were females. Epilepsy was focal in 11, generalized in 6, and mixed in 3. Average dose was 3.9 mg/kg/d. The mean duration of treatment was 8.2 months. Eight had greater than 50% decrease in seizure frequency, of which 7 had focal epilepsy, and 1 had Lennox-Gastaut/mixed epilepsy. Two had drowsiness and 3 behavioral complaints. One experienced tingling and dizziness. Our retrospective review suggests that brivaracetam is an effective therapy for refractory focal epilepsy in children older than 4 years of age.
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Affiliation(s)
- Sara McGuire
- Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Gustavo Silva
- Department of Neurology, Hahnemann University Hospital, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Darshan Lal
- Department of Neurology, Hahnemann University Hospital, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Divya S Khurana
- Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.,Deceased
| | - Agustin Legido
- Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Daphne Hasbani
- Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Karen S Carvalho
- Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Joseph Melvin
- Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Ignacio Valencia
- Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
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Abstract
PURPOSE OF REVIEW The treatment of epilepsy in children is highly individualized at each and every major step in the management. This review examines various factors that modify the treatment from the point of initiation of therapy to the decision to stop an antiepileptic drug (AED). RECENT FINDINGS AED therapy leads to seizure freedom in about 70% of all children with epilepsy. AED initiation could be delayed until a second seizure in most children and may be avoided altogether in many children with self-limited childhood focal epilepsies. Three key factors influence the choice of AED: seizure type(s), efficacy of the drug for the seizure type, and the side effect profile of the drug(s). For epileptic spasms, steroids and vigabatrin are the most effective treatment options. For absence seizures, ethosuximide and valproic acid are superior to lamotrigine. For focal seizures, many newer AEDs have favorable side effect profiles with efficacy comparable to older-generation drugs. For generalized epilepsies, valproic acid remains the most effective drug for a broad range of seizure types. Genetic and metabolic etiologies may guide unique treatment choices in some children. After 2 years or more of seizure freedom, if the recurrence risk after AED withdrawal is acceptable, slow weaning of AEDs should be done over the span of 6 weeks or longer. After discontinuation, about 70% of patients remain seizure free, and of those with recurrence, the majority achieve seizure control with restarting an AED. When treatment with two or more AEDs fails, other treatment opportunities for drug-resistant epilepsy, including epilepsy surgery, vagal nerve stimulation, and dietary therapies should be considered. SUMMARY Carefully selected medical therapy guided by seizure type and AED characteristics is effective in more than two-thirds of children with epilepsy.
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21
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Málaga I, Sánchez-Carpintero R, Roldán S, Ramos-Lizana J, García-Peñas JJ. New anti-epileptic drugs in paediatrics. An Pediatr (Barc) 2019. [DOI: 10.1016/j.anpede.2019.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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22
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Pressler RM, Lagae L. Why we urgently need improved seizure and epilepsy therapies for children and neonates. Neuropharmacology 2019; 170:107854. [PMID: 31751548 DOI: 10.1016/j.neuropharm.2019.107854] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/22/2019] [Accepted: 11/15/2019] [Indexed: 12/16/2022]
Abstract
In contrast to epilepsy in adolescents and adults, neonatal seizures and early onset epilepsy poses unique challenges with significant repercussion for treatment choices. Most importantly, high seizure burden and epileptic encephalopathy are associated with developmental, behavioural and cognitive problems. The causes are multifactorial and include etiology, seizure burden, epileptic encephalopathy, but also antiseizure medication. In contrast to adults and older children only very few drugs have been licenced for infants and neonates, and after a long delay. Very recently, extrapolation of adult data has become possible as a path to speed up drug development for younger children but this is not necessarily possible for infants and neonates. With the advances in understanding the molecular basis of many epilepsies, targeted therapies become available, for example for KCNQ2 mutation related epilepsies, Dravet syndrome or tuberous sclerosis complex. Drug trials in neonates are particularly challenging because of their inconspicuous clinical presentation, the need for continuous EEG monitoring, high co-morbidity, and poor response to antiepileptic drugs. There is an urgent need for development of new drugs, evaluation of safety and efficacy of current antiseizure drugs, as well as for national policies and guidelines for the management of seizures and epilepsy in neonates and infants. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
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Affiliation(s)
- Ronit M Pressler
- Neuroscience Unit, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
| | - Lieven Lagae
- Department Paediatric Neurology, University Hospitals, Leuven, Belgium
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23
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Abram M, Jakubiec M, Kamiński K. Chirality as an Important Factor for the Development of New Antiepileptic Drugs. ChemMedChem 2019; 14:1744-1761. [PMID: 31476107 DOI: 10.1002/cmdc.201900367] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/26/2019] [Indexed: 12/17/2022]
Abstract
In recent years, chiral molecules (especially enantiomers) have occupied a significant place in pharmaceutical industry and have played a prominent role in the development of new drugs. Individual stereoisomers exhibit marked differences in pharmacodynamic, pharmacokinetic, and toxicological properties. Therefore, there is currently considerable interest in fully characterizing and examining both enantiomers in the early stages of new drug development. Despite the fact that epilepsy is a complex disease and that a given drug's mechanism of action may be multidirectional and not always fully understood, significant differences have been observed in the anticonvulsant activity of individual stereoisomers. Therefore, between 1996 and 2018, among 14 new antiepileptic drugs (AEDs) approved for the treatment of epilepsy, as many as seven are chiral and introduced to the market in the single-enantiomer (or diastereomer) form. This review provides an overview of the impact of chirality on the development and discovery of new AEDs that have entered into clinical trials or preclinical studies. These new AEDs were developed by applying the single-enantiomer approval strategy. Herein we focus our attention on the main synthetic pathways of stereoisomers, as well as on the influence of chirality on pharmacodynamic, pharmacokinetic, and/or toxicological properties.
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Affiliation(s)
- Michał Abram
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, Medyczna 9, 30-688, Kraków, Poland
| | - Marcin Jakubiec
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, Medyczna 9, 30-688, Kraków, Poland
| | - Krzysztof Kamiński
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, Medyczna 9, 30-688, Kraków, Poland
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24
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Arzimanoglou A, Kalilani L, Anamoo MA, Cooney M, Golembesky A, Taeter C, Bozorg A, Tofighy A, Wheless J. Role of observational studies in supporting extrapolation of efficacy data from adults to children with epilepsy - A systematic review of the literature using lacosamide as an example. Eur J Paediatr Neurol 2019; 23:589-603. [PMID: 31171490 DOI: 10.1016/j.ejpn.2019.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/08/2019] [Accepted: 05/06/2019] [Indexed: 12/31/2022]
Abstract
Extrapolation of efficacy data from adults to children is accepted for focal epilepsy - the antiepileptic drug, lacosamide, has been approved for the treatment of children ≥4 years of age on this basis. Since many small-scale, open-label studies are reported in the literature before approval, a systematic review was conducted to ascertain whether results of these could be used to support extrapolation in epilepsy in the future. In the absence of randomised trials, a second analysis was conducted for reports on lacosamide use in adults with generalized epilepsies. Twenty-seven articles were included in the paediatric qualitative synthesis, and 14 in the adult. Paediatric studies were analysed separately based on seizure type: focal, generalised and mixed. In focal epilepsy, safety and seizure-related findings mirrored those observed in the adult Phase II/III trials, supporting the feasibility of data extrapolation. Few studies reported outcomes in children with epilepsies associated with generalised seizures, and those that included children with different seizure types, mostly did not provide results separately. Lacosamide treatment appeared beneficial for children and adults experiencing tonic-clonic and myoclonic seizures. Reports of seizure aggravation were inconsistent and, in many cases, could not be clearly attributed to lacosamide. Given the absence of sufficient data, evidence for the feasibility of extrapolation was not as clear-cut as it was in focal epilepsy. These results highlight the complexities of conducting trials in the generalised epilepsy setting, and the importance of studies in the real-life setting and of analysing efficacy data per generalized seizure type and syndrome.
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Affiliation(s)
- A Arzimanoglou
- Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, European Reference Network EpiCARE, University Hospital of Lyon, Lyon, France; Universitat de Barcelona, Department of Child Neurology, Epilepsy Unit, European Reference Network ERN EpiCARE, Hospital San Juan de Deu, Barcelona, Spain.
| | | | | | | | | | | | | | | | - J Wheless
- Chief of Pediatric Neurology, University of Tennessee Health Science Center, Director, Neuroscience Institute and Le Bonheur Comprehensive Epilepsy Program, Le Bonheur Children's Hospital, Memphis, TN, USA
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Gaudio E, Gienapp AJ, Wheless J. Perampanel Pharmacokinetics in Children: Correlation of Dose With Serum Concentrations. J Child Neurol 2019; 34:427-431. [PMID: 30909831 DOI: 10.1177/0883073819837465] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Enzyme-inducing antiseizure drugs taken concomitantly with perampanel are known to influence perampanel serum concentrations. In this study, we examined perampanel dosage, serum concentrations, and the effect of concomitant enzyme-inducing antiseizure drugs in children for a 3-year period. A retrospective chart review determined patient age, weight, perampanel serum concentration and prescribed dose, and concomitant drugs. Of 87 patients included in the study, 41 were prescribed an enzyme-inducing antiseizure drug. Although perampanel dosage did not differ between patients prescribed/not prescribed enzyme-inducing antiseizure drugs, serum concentrations were significantly lower in patients taking enzyme-inducing antiseizure drugs (average serum concentration for the enzyme-inducing antiseizure drug group was still above the previously reported efficacious serum concentration of 70 ng/mL). Although perampanel serum concentrations are negatively influenced by enzyme-inducing antiseizure drugs in children, it is likely that efficacy would be improved in patients not concomitantly prescribed enzyme-inducing antiseizure drugs because pediatric perampanel dosing is similar to that reported in prior adult efficacy trials.
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Affiliation(s)
| | - Andrew J Gienapp
- 2 Le Bonheur Children's Hospital Neuroscience Institute, Memphis, TN, USA.,3 Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - James Wheless
- 2 Le Bonheur Children's Hospital Neuroscience Institute, Memphis, TN, USA.,4 Division of Pediatric Neurology, University of Tennessee Health Science Center, Memphis, TN, USA
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van den Anker J. Paediatric extrapolation: the panacea for paediatric drug development? Br J Clin Pharmacol 2018; 85:672-674. [PMID: 30536691 DOI: 10.1111/bcp.13836] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023] Open
Affiliation(s)
- John van den Anker
- Paediatric Pharmacology and Pharmacometrics Research Program, University of Basel Children's Hospital, Basel, Switzerland.,Division of Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA
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Schubert-Bast S, Willems LM, Kurlemann G, Knake S, Müller-Schlüter K, Rosenow F, Strzelczyk A. Postmarketing experience with brivaracetam in the treatment of focal epilepsy in children and adolescents. Epilepsy Behav 2018; 89:89-93. [PMID: 30390435 DOI: 10.1016/j.yebeh.2018.10.018] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 10/14/2018] [Accepted: 10/15/2018] [Indexed: 11/28/2022]
Abstract
INTRODUCTION This multicenter, retrospective study aimed to evaluate the efficiency, retention, safety, and tolerability of brivaracetam (BRV) in children and adolescents with focal epilepsy. METHODS All patients aged ≤17 years with focal epilepsy who started BRV in 2016 and 2017 were analyzed. RESULTS Thirty-four patients (mean age: 12.2 years, range: 3-17 years, 56% female) were treated with BRV for 25 days to 24 months, with a total exposure time of 19.7 years. Overnight switch from levetiracetam (LEV) to BRV was performed in 20 patients at a median ratio of 10:1. Retention rate was 97% at three months, with only one patient reporting a discontinuation of BRV treatment. Further dropouts were reported in one patient after seven months and in two patients after one year of treatment, respectively. The median length of exposure to BRV was 180 days. Efficacy at three months was 47% (50% responder rate), with 10 patients (29%) reporting seizure freedom. A long-term 50% responder rate was present in 12 patients [35%; four patients seizure-free (12%)] for more than six months and in seven patients (21%; no seizure-free patients) for more than 12 months. Treatment-emergent adverse events were observed in 12% of patients, with the most common being sedation, somnolence, loss or gain of appetite, and psychobehavioral adverse events. CONCLUSIONS Use of BRV in children and adolescents seems to be safe and well-tolerated. The results with 50% responder rate of 47% are consistent with those from randomized controlled trials and postmarketing studies in adults. An immediate switch from LEV to BRV at a ratio of 10:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV and a switch to BRV can be considered in patients with LEV-induced adverse events.
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Affiliation(s)
- Susanne Schubert-Bast
- Department of Neuropediatrics, Goethe-University, Frankfurt am Main, Germany; Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany
| | - Laurent M Willems
- Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany
| | - Gerhard Kurlemann
- Department of Neuropediatrics, Westfälische Wilhelms-University, Münster, Germany
| | - Susanne Knake
- Epilepsy Center Hessen and Department of Neurology, Philipps-University, Marburg, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany
| | - Karen Müller-Schlüter
- Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, Neuruppin, Germany
| | - Felix Rosenow
- Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany
| | - Adam Strzelczyk
- Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany; Epilepsy Center Hessen and Department of Neurology, Philipps-University, Marburg, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany.
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Abstract
Lacosamide (Vimpat®) is a functionalized amino acid (available orally and intravenously) approved in the EU and the USA for use as monotherapy and adjunctive therapy for the treatment of focal-onset seizures in adults, adolescents and children aged ≥ 4 years with epilepsy. In adults and adolescents (aged ≥ 16 years), oral lacosamide as adjunctive therapy to other antiepileptic drugs was generally effective in reducing seizure frequency during short-term (up to 18 weeks) treatment, with efficacy sustained over the longer-term (up to 8 years). Moreover, patients were effectively switched from adjunctive oral lacosamide to the same dosage of intravenous lacosamide. Oral lacosamide was an effective conversion to monotherapy agent in this patient population and as monotherapy demonstrated noninferiority to carbamazepine controlled release in terms of seizure freedom. Antiepileptic benefits were maintained during longer-term (≤ 2 years) monotherapy. The antiepileptic efficacy of lacosamide in children aged ≥ 4 years has been extrapolated from data from adults and adolescents, with a similar response expected provided paediatric dosage adaptations are used and safety is demonstrated. Indeed, preliminary data demonstrated the efficacy of short-term (16 weeks) adjunctive lacosamide in patients aged ≥ 4 to < 17 years. Oral lacosamide was generally well tolerated over the short- and longer-term when administered as adjunctive therapy, a conversion to monotherapy agent and monotherapy in adults and adolescents and when administered as adjunctive therapy in children aged ≥ 4 years. Thus, lacosamide is a useful option for the management of focal-onset seizures across a broad age range, starting as early as 4 years of age.
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Affiliation(s)
- Sheridan M Hoy
- Springer, Private Bag 65901, Mairangi Bay, Auckland 0754, New Zealand.
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