5 years ago

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children

Gérard Pons, Vincent Jullien, Olivier Dulac, Christelle Rodrigues, Emmanuelle Comets, Elisabeth Rey, Catherine Chiron
Aims Oxcarbazepine 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 in order to evaluate the consistency between the recommended pediatric doses and the reference range for trough concentration (Ctrough) of MHD (3-35 mg/L). Methods A total of 279 plasma samples were obtained from 31 epileptic children (2-12y) after a single dose of oxcarbazepine. Concentration-time data were analyzed with Monolix 4.3.2. The probability to obtain Ctrough between 3-35 mg/L was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg/kg/day. Results A 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/70kg, 337 L/70kg, 60.7 L, and 62.5 L/h respectively. Typical values for MHD clearance and distribution volume were 4.11 L/h/70kg and 54.8 L/70kg 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/day instead of the recommended target maintenance dose (30-45 mg/kg/day) to obtain Ctrough within the reference range. By contrast, 10kg children with EIAEDs would need 90 mg/kg/day instead of the maximum recommended dose of 60 mg/kg/day. Conclusion This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10kg children with concomitant EIAEDS and 50kg children without EIAEDs.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13392

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