Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children

Autor: Christelle Rodrigues, Vincent Jullien, Olivier Dulac, Gérard Pons, Catherine Chiron, Elisabeth Rey, Emmanuelle Comets
Přispěvatelé: Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Rok vydání: 2017
Předmět:
Zdroj: British Journal of Clinical Pharmacology
British Journal of Clinical Pharmacology, Wiley, 2017, 83 (12), pp.2695-2708. ⟨10.1111/bcp.13392⟩
British Journal of Clinical Pharmacology, 2017, 83 (12), pp.2695-2708. ⟨10.1111/bcp.13392⟩
ISSN: 1365-2125
0306-5251
DOI: 10.1111/bcp.13392
Popis: International audience; AimsOxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (Ctrough) of MHD (3–35 mg l–1).MethodsA total of 279 plasma samples were obtained from 31 epileptic children (age 2–12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain Ctrough between 3–35 mg l–1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg–1 day–1.ResultsA parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h–1 70 kg–1, 337 l 70 kg–1, 60.7 l and 62.5 l h–1, respectively. Typical values for MHD clearance and distribution volume were 4.11 l h–1 70 kg–1 and 54.8 l 70 kg–1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20–30 mg kg–1 day–1 instead of the recommended target maintenance dose (30–45 mg kg–1 day–1) to obtain Ctrough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg–1 day–1 instead of the maximum recommended dose of 60 mg kg–1 day–1.ConclusionThis population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs.
Databáze: OpenAIRE
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