Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

ABSTRACT

Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size.

Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation.

Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.

KEYWORDS:

• Antiepileptic drugs
• dose rationale
• epilepsy
• epileptic seizures
• modelling and simulation
• paediatrics
• personalised medicine
• pharmacokinetics
• pharmacokinetic-pharmacodynamic relationships
• translational pharmacology

Article highlights

• Despite the development of therapeutic guidelines for the treatment of epileptic seizures, AED selection and dose rationale for children remains empirical.

• The use of dosing regimens in mg/kg does not correct for age-related changes in pharmacokinetics and pharmacodynamics in children, especially if one considers the use of polytherapy with two or more AEDs.

• Inter- and intraindividual differences in pharmacokinetics and pharmacodynamics of AEDs need to be taken into account for the personalization of treatment in pediatric epilepsy.

• Whilst the identification of predictive biomarkers remains a challenging endeavor, quantitative clinical pharmacology methods can provide guidance for both anti-epileptic drug and dose selection. These methods allow for evidence synthesis, integration, and extrapolation of findings across different age groups, enabling better clinical decision-making and improved therapeutic response in children.

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Declaration of interest

SC van Dijkman has been funded by FP7 project (Global Research in Paediatrics (GRIP). O Della Pasqua is a member of GRiP and is also Senior Director Clinical Pharmacology at GlaxoSmithkline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Additional information

Funding

The research leading to these results has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 261060 (Global Research in Paediatrics – GRiP network of excellence).