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

Arzimanoglou, Alexis; Kalilani, Linda; Anamoo, M.A.; Cooney, Maureen; Golembesky, Amanda; Taeter, C.; Bozorg, Ali; Tofighy, Azita; Wheless, James W.

doi:10.1016/j.ejpn.2019.05.002

Cited by 7 publications

(3 citation statements)

References 59 publications

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“…This is demonstrated by Arzimanoglou et al where they concluded that there is sufficient literature and data on extrapolating lacosamide dosing to pediatric populations with FOS but the feasibility of extrapolation was difficult in the setting of other epilepsy types. 94 Third, ASMs are generally titrated to effect in clinical practice and it is often difficult to collect this information with sparse sampling and opportunistic studies. Unless a patient is taking a narrow therapeutic index drug such as phenobarbital or phenytoin, where drug levels are associated with efficacy and toxicity, most ASMs may have a limited correlation between plasma concentrations and efficacy or toxicity.…”

Section: Current Challenges and Future Directionsmentioning

confidence: 99%

“…This is demonstrated by Arzimanoglou et al. where they concluded that there is sufficient literature and data on extrapolating lacosamide dosing to pediatric populations with FOS but the feasibility of extrapolation was difficult in the setting of other epilepsy types 94 . Third, ASMs are generally titrated to effect in clinical practice and it is often difficult to collect this information with sparse sampling and opportunistic studies.…”

Section: Current Challenges and Future Directionsmentioning

confidence: 99%

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Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population

Maglalang,

Wen,

Hornik

et al. 2024

Clinical Translational Sci

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Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug–drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.

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Section: Current Challenges and Future Directionsmentioning

confidence: 99%

Section: Current Challenges and Future Directionsmentioning

confidence: 99%

Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population

Maglalang,

Wen,

Hornik

et al. 2024

Clinical Translational Sci

View full text Add to dashboard Cite

show abstract

“…Because of the methodological and ethical challenges associated with randomized, placebo-controlled trials in children, ASMs are typically first tested and licensed in adults, and it may take years before a new drug is approved in children and infants (6,(13)(14)(15)(16). Off-label ASM use in children is therefore common (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Treatment of Focal-Onset Seizures in Children: Should This Be More Etiology-Driven?

2022

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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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Why we urgently need improved seizure and epilepsy therapies for children and neonates

Pressler

Lagae

2020

Neuropharmacology

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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. Highlights  Treatment of early onset seizures and epilepsies pose a clinical challenge to clinicians.  Only very few drugs have been licenced due to lack of randomised controlled trials.  Systematic reviews no good evidence for the choice of treatment.  Precision medicine is so far only available for a small number of syndromes.

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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

Abstract: article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 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.

Cited by 7 publications

References 59 publications

Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population

Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population

Treatment of Focal-Onset Seizures in Children: Should This Be More Etiology-Driven?

Why we urgently need improved seizure and epilepsy therapies for children and neonates

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