Population Pharmacokinetics of Antiepileptic in Pediatrics (EPIPOP)

The purpose of this study is to develop population pharmacokinetic models for antiepileptic drugs in a pediatric population.

The interest of these models is multiple:

• describe the pharmacokinetics of these molecules in children and explain the inter-individual variability of concentrations through covariates such as weight, age, co-treatments, genetic polymorphisms and renal function;
• estimate maximum, minimum and exposure concentrations from the individual pharmacokinetic parameters for each patient;
• propose adaptations of doses for certain classes of children (according to age, weight etc.) and individualize the doses.

Study Overview

• Status: Completed
• Conditions: Epilepsy
• Intervention / Treatment: Biological: Valproic acid; Biological: carbamazepine; Biological: phenobarbital; Biological: phenytoin; Biological: levetiracetam; Biological: lamotrigine; Biological: topiramate; Biological: oxcarbazepine; Biological: stiripentol; Biological: clobazam; Biological: brivaracétam; Biological: felbamate; Biological: lacosamide; Biological: rufinamide; Biological: gabapentine; Biological: pregabaline; Biological: sultiame; Biological: tiagabine; Biological: vigabatrine; Biological: mesuximide; Biological: primidone; Biological: perampanel; Biological: ethosuximide; Biological: zonisamide; Biological: cannabidiol; Other: genetic polymorphisms

Detailed Description

Epilepsy affects about 1% of the population, with a peak incidence in childhood, and persistent seizures on antiepileptic therapy in approximately 30% of patients. Over the past two decades, many antiepileptic molecules have emerged, raising the question of their optimal use, especially in pediatrics, where pharmacokinetics and pharmacodynamics are different from adults and largely influenced by age and development.

The pharmacokinetics of antiepileptics have been little studied in pediatric populations. In children, it is important to know if a maturational effect (of age) has to be taken into account in addition to the physiological effect (of the weight) to adapt the doses. Moreover, these molecules are often used in combination and lot of enzyme interactions make their use delicate. All of these factors explain the existence of significant inter-individual variability in the pediatric population.

The implication of the demographic and medicinal factors mentioned above, as well as the balance of efficacy / undesirable effects, justify the interest of a pharmacological monitoring of these drugs in a pediatric population. The use of population pharmacokinetics is particularly interesting in children because it requires only a small number of samples per patient and can be used to describe the predominant inter-individual variability in this population.

The main goal is to develop population pharmacokinetic models for the following antiepileptic drugs in children: valproic acid, carbamazepine, phenobarbital, phenytoin, levetiracetam, lamotrigine, topiramate, oxcarbazepine, stiripentol, clobazam, brivaracétam, felbamate, lacosamide, rufinamide, gabapentine, pregabaline, sultiame, tiagabine, vigabatrine, mesuximide, primidone, perampanel, ethosuximide, zonisamide and cannabidiol. The interest of these models is multiple:

• describe the pharmacokinetics of these molecules in children and explain the interindividual variability of concentrations through covariates such as weight, age, co-treatments, genetic polymorphisms and renal function;
• estimate maximum, minimum and exposure concentrations from the individual pharmacokinetic parameters for each patient;
• propose adaptations of doses for certain classes of children (according to age, weight etc.) and individualize the doses.

The secondary objectives of this work are:

• Build models jointly with several antiepileptic drugs, accounting for the strength of interactions between them during multiple therapies.
• Link antiepileptic concentrations to the effects of treatment (reduction or cessation of seizures): pharmacokinetic-pharmacodynamic study with concentration / efficacy and concentration / toxicity relationships.
• The evaluation of preexisting models in the literature and the comparison of the data with the results of these models (external validation).

Pharmaco-statistical analysis will be carried out on the retrospective data of patients treated with one or more antiepileptic molecule (s) and whose blood dosage of the drug(s) as part of their therapeutic follow-up is available. The study of genetic polymorphisms will be carried out from available blood samples, collected and stored as part of therapeutic follow-up of patients.

• Study Type: Observational
• Enrollment (Actual): 753

Contacts and Locations

Study Locations

• France
  • Paris, France, 75014
    • AP-HP Cochin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 14 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Minor patient treated by one or more antiepileptics and for which a blood test has been performed

Description

Inclusion Criteria:

• Children from 0 to 18 years of age with epilepsy;
• Treatment with one or more antiepileptic drug (s) studied (valproic acid, carbamazepine, phenobarbital, phenytoin, levetiracetam, lamotrigine, topiramate, oxcarbazepine, stiripentol, clobazam, brivaracétam, felbamate, lacosamide, rufinamide, gabapentine, pregabaline, sultiame, tiagabine, vigabatrine, mesuximide, primidone, perampanel, ethosuximide, zonisamide and cannabidiol);
• Blood dosage of the drug (s) as part of their therapeutic follow-up in the Pharmacology laboratory of the Cochin hospital between 2007 and 2019

Exclusion Criteria:

• patient with missing data on time of last drug taking, time of collection, co-treatments and / or dose administered;
• patient with doubt about compliance

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
antiepileptics titration; Titration of valproic acid, carbamazepine, phenobarbital, phenytoin, levetiracetam, lamotrigine, topiramate, oxcarbazepine, stiripentol, clobazam, brivaracétam, felbamate, lacosamide, rufinamide, gabapentine, pregabaline, sultiame, tiagabine, vigabatrine, mesuximide, primidone, perampanel, ethosuximide, zonisamide and cannabidiol	Biological: Valproic acid; titration; Biological: carbamazepine; titration; Biological: phenobarbital; titration; Biological: phenytoin; titration; Biological: levetiracetam; titration; Biological: lamotrigine; titration; Biological: topiramate; titration; Biological: oxcarbazepine; titration; Biological: stiripentol; titration; Biological: clobazam; titration; Biological: brivaracétam; titration; Biological: felbamate; titration; Biological: lacosamide; titration; Biological: rufinamide; titration; Biological: gabapentine; titration; Biological: pregabaline; titration; Biological: sultiame; titration; Biological: tiagabine; titration; Biological: vigabatrine; titration; Biological: mesuximide; titration; Biological: primidone; titration; Biological: perampanel; titration; Biological: ethosuximide; titration; Biological: zonisamide; titration; Biological: cannabidiol; titration
antiepileptics titration and available blood samples; Titration of valproic acid, carbamazepine, phenobarbital, phenytoin, levetiracetam, lamotrigine, topiramate, oxcarbazepine, stiripentol, clobazam, brivaracétam, felbamate, lacosamide, rufinamide, gabapentine, pregabaline, sultiame, tiagabine, vigabatrine, mesuximide, primidone, perampanel, ethosuximide, zonisamide and cannabidiol	Biological: Valproic acid; titration; Biological: carbamazepine; titration; Biological: phenobarbital; titration; Biological: phenytoin; titration; Biological: levetiracetam; titration; Biological: lamotrigine; titration; Biological: topiramate; titration; Biological: oxcarbazepine; titration; Biological: stiripentol; titration; Biological: clobazam; titration; Biological: brivaracétam; titration; Biological: felbamate; titration; Biological: lacosamide; titration; Biological: rufinamide; titration; Biological: gabapentine; titration; Biological: pregabaline; titration; Biological: sultiame; titration; Biological: tiagabine; titration; Biological: vigabatrine; titration; Biological: mesuximide; titration; Biological: primidone; titration; Biological: perampanel; titration; Biological: ethosuximide; titration; Biological: zonisamide; titration; Biological: cannabidiol; titration; Other: genetic polymorphisms; genetic polymorphisms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Volume of distribution	through study completion, an average of 5 years
Absorption constant	through study completion, an average of 5 years
Clearance	through study completion, an average of 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite measure of the inter-individual variability	Covariates of inter-individual variability : age, weight, co-treatments, genetic polymorphisms and renal function	through study completion, an average of 5 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Principal Investigator: Jean-Marc TRELUYER, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2017
• Primary Completion (Actual): June 15, 2023
• Study Completion (Actual): June 15, 2023

Study Registration Dates

• First Submitted: June 20, 2017
• First Submitted That Met QC Criteria: June 20, 2017
• First Posted (Actual): June 22, 2017

Study Record Updates

• Last Update Posted (Actual): November 20, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: children; pharmacokinetics; genetic polymorphisms; antiepileptics
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Fatty Acids; Lipids; Azoles; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Carbohydrates; Acids, Acyclic; Carboxylic Acids; Imidazoles; Amides; Amines; Piperidines; Amino Acids; Pyrimidines; Pentanoic Acids; Valerates; Fatty Acids, Volatile; Triazines; Alcohols; Glycols; Genetic Phenomena; Pyrimidinones; Benzazepines; gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Sugars; Propylene Glycols; Pyrrolidines; Acids, Carbocyclic; Acetamides; Acetates; Sulfonamides; Sulfones; Cannabinoids; Benzodiazepines; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Cyclohexanecarboxylic Acids; Acids, Heterocyclic; Hexoses; Monosaccharides; Carbamates; Genetic Variation; Pyrrolidinones; Fructose; Ketoses; Isoxazoles; Imides; Hydantoins; Imidazolidines; Barbiturates; Phenylcarbamates; Nipecotic Acids; Succinimides; Gabapentin; Lamotrigine; Lacosamide; Zonisamide; Levetiracetam; Oxcarbazepine; Topiramate; Clobazam; Tiagabine; Felbamate; Cannabidiol; Valproic Acid; Carbamazepine; Phenytoin; Phenobarbital; Ethosuximide; Primidone; Vigabatrin; stiripentol; rufinamide; sulthiame; methsuximide; perampanel; Polymorphism, Genetic
• Other Study ID Numbers: NI17009HLJ

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No