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.