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, Contrairement à l'étude antérieure, nous avons pu quantifier les besoins posologiques selon le poids de l'enfant et le co-traitement, montrant l'intérêt de l'approche de population par rapport à l'analyse noncompartimentale, la dose/kg doit aussi être plus élevée

V. Concernant-le, Avec ces données, un modèle de population a été développé pour une formulation récente à libération prolongée. Il s'agit d'un modèle monocompartimental dont la constante d'absorption est contrainte à être supérieure à la constante d'élimination pour pallier au flip-flop et obtenir les vraies valeurs de paramètres PK. L'importante liaison du VPA aux protéines plasmatiques a été tenue en compte via l'équation de Langmuir et a permis d'obtenir une estimation des concentrations et paramètres libres. A partir de simulations de Monte Carlo, nous avons pu évaluer les recommandations posologiques actuelles. Les recommandations européennes (dose de maintenance entre 20 et 30 mg/kg/jour) (Résumé des caractéristiques du produit, 2013) semblent adéquates pour les enfants de ? 20kg, mais peut-être pas suffisantes pour les enfants de < 20 kg pour qui 40 mg/kg/jour permet d'obtenir une plus grande probabilité d'avoir des concentrations résiduelles dans la zone cible. Nos résultats vont, provenant de deux études, ont été inclus dans la base de données, 2015.

. Ueshima, 2008) a permis de prédire la fraction libre du VPA. Les résultats ont remis en question l'utilisation d'une zone thérapeutique cible en terme de concentration totale, Malgré l'absence de concentrations libres, l'utilisation de l'équation de Langmuir (Holford, 2011) conjointement aux valeurs de Bmax et Kd décrites dans la littérature

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, protocole la rend donc plus éthique et moins coûteuse. L'EMA encourage ainsi l'utilisation de cette méthodologie, a fortiori lors de la conduite d'études cliniques chez l'enfant

. Al-banna, but étant de minimiser la matrice de variance-covariance des paramètres, l'optimisation des protocoles peut se baser sur la Mf pour y parvenir. En effet, d'après l'inégalité de Rao-Cramer, l'inverse de la Mf est la borne inférieure de la matrice de variance, La recherche du protocole optimal, i.e. qui permet la plus petite incertitude sur les paramètres estimés, peut être réalisée par simulations de protocoles. Cependant, malgré des résultats intéressants, 1990.

, La connaissance préalable du modèle et des paramètres PK est donc nécessaire pour optimiser un protocole. Ainsi, pour calculer les critères d'optimalité, il faut exploiter les résultats obtenus lors d'études de population antérieures ou d'études d'extrapolation pour chercher un protocole qui maximise la Mf et donc minimise les variances d'estimation (les SE)

, Comme il n'existe pas d'expression analytique pour la vraisemblance ni de la Mf , due à la non-linéarité du modèle. L'approche actuellement utilisée dans les différents logiciels d'estimation est de linéariser le modèle autour des effets aléatoires attendus

C. Peigné, S. Chhun, M. Tod, E. Rey, C. Rodrigues et al., Population Pharmacokinetics of Stiripentol in Paediatric Patients with Dravet Syndrome Treated with Stiripentol, Valproate and Clobazam Combination Therapy, Clin Pharmacokinet, 2018.

, , vol.57, pp.739-748