Christelle Rodrigues1, Stéphanie Chhun2, Catherine Chiron1, Olivier Dulac1, Elisabeth Rey1, Gérard Pons1, Vincent Jullien3,4. 1. INSERM U1129, Paris Descartes University, CEA, Gif-sur-Yvette, Paris, France. 2. Hôpital Necker-Enfants Malades - Enfants Malades, Inserm U1151, INEM, Laboratoire d'immunologie biologique, Assistance Publique - Hôpitaux de Paris, Paris, France. 3. INSERM U1129, Paris Descartes University, CEA, Gif-sur-Yvette, Paris, France. vincent.jullien@aphp.fr. 4. Service de Pharmacologie, Hôpital Européen Georges Pompidou, 20 Rue Leblanc, 75015, Paris, France. vincent.jullien@aphp.fr.
Abstract
PURPOSE: The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100 mg/L). METHODS: Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg. RESULTS: A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. CONCLUSIONS: If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.
PURPOSE: The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100 mg/L). METHODS: Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg. RESULTS: A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. CONCLUSIONS: If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.
Entities:
Keywords:
Childhood epilepsy; Population pharmacokinetics; Protein binding; Valproate
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