Population pharmacokinetics of the sustained-release granule formulation of valproic acid in epileptic children
Rodrigues Christelle(1), Chhun Stéphanie(2), Chiron Catherine(1), Dulac Olivier(1), Rey Elisabeth(1), Pons Gérard(1), Jullien Vincent(1, 3)
(1) INSERM U1129, Paris, France; Paris Descartes University; CEA, Gif-sur-Yvette, France (2) Assistance Publique – Hôpitaux de Paris, Hôpital Necker-Enfants Malades – Enfants Malades, Inserm U1151, INEM, Laboratoire d’immunologie biologique, Paris, France (3) Service de Pharmacologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
Objectives: Valproic acid (VPA) is an antiepileptic drug widely used in pediatric population. A prolonged-release granule formulation facilitating drug intake by children is available at a recommended mean daily dose between 20 and 30 mg/kg [1,2]. The objective of this work was to develop a population pharmacokinetic model for this formulation in epileptic children and to use this model to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100 mg/L) [3].
Methods: 98 children (1 - 17.6 years) were included in the study providing 325 plasma samples. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50-100 mg/L was determined by Monte Carlo simulations for doses of 20, 30 and 40 mg/kg/day and body weights between 10 and 70 kg.
Results: VPA data were best described by a one compartment model with first-order absorption and elimination and flip-flop parametrization. Typical values for VPA clearance and volume of distribution were 0.672 L/h/70kg and 13.2 L/70kg respectively. Both parameters were related to body weight via allometric models. Total daily dose also influenced VPA clearance, representing the saturable plasma protein binding of VPA [4]. A 40 mg/kg daily dose was needed for 10 kg children to obtain a Ctrough within the target range, whereas daily doses of 30 mg/kg and 20 mg/kg were found appropriate for 20 kg and > 20 kg children respectively.
Conclusions: Here was developed the first population pharmacokinetic model for VPA when given as a prolonged-release granule formulation. Current dosing recommendations were found appropriate except for small children (10kg) who could need higher doses than those currently recommended.
References:
[1] Résumé des caractéristiques du produit. Micropakine L.P. 2013.
[2] Summary of Product Characteristics. Epilim Chronosphere. 2015.
[3] Patsalos PN, Berry DJ, Bourgeois BFD, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E. Antiepileptic drugs - best practice guidelines for therapeutic drug monitoring : A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239–76.
[4] Herngren L, Lundberg B. Pharmacokinetics of total and free valproic acid during monotherapy in infants. J Neurol. 1991;238:315–9.
