Rodrigues Christelle, Chiron Catherine, Rey Elisabeth, Dulac Olivier, Comets Emmanuelle, Pons Gérard, Jullien Vincent
INSERM U1129, Paris, France.
Paris Descartes University, CEA, Gif-sur-Yvette, France.
Br J Clin Pharmacol. 2017 Dec;83(12):2695-2708. doi: 10.1111/bcp.13392. Epub 2017 Sep 20.
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 to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (C ) of MHD (3-35 mg l ).
A 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 C between 3-35 mg l was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg day .
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 70 kg , 337 l 70 kg , 60.7 l and 62.5 l h , respectively. Typical values for MHD clearance and distribution volume were 4.11 l h 70 kg and 54.8 l 70 kg 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 C within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg day instead of the maximum recommended dose of 60 mg kg day .
This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs.
奥卡西平是一种抗癫痫药物，其活性主要归因于其单羟基衍生物代谢物（MHD）。建立了儿童的母体-代谢物群体药代动力学模型，以评估推荐的儿科剂量与MHD谷浓度（C）参考范围（3 - 35 mg/L）之间的一致性。
从31名癫痫儿童（年龄2 - 12岁）单次服用奥卡西平后采集了279份血浆样本。浓度-时间数据用Monolix 4.3.2进行分析。通过蒙特卡罗模拟确定了剂量范围为10至90 mg/kg·天的情况下，获得3 - 35 mg/L的C的概率。
一个包含奥卡西平两个房室和MHD一个房室的母体-代谢物模型最能描述这些数据。奥卡西平清除率、中央和周边分布容积以及分布清除率的典型值分别为140 L/h·70 kg、337 L/70 kg、60.7 L和62.5 L/h。MHD清除率和分布容积的典型值分别为4.11 L/h·70 kg和54.8 L/70 kg。奥卡西平和MHD的清除率及分布容积通过经验异速生长模型与体重相关。酶诱导抗癫痫药物（EIAEDs）使MHD清除率提高了29.3%。体重50 kg且未使用EIAEDs的儿童可能需要20 - 30 mg/kg·天，而不是推荐的目标维持剂量（30 - 45 mg/kg·天），以在参考范围内获得C。相比之下，体重10 kg且使用EIAEDs的儿童需要90 mg/kg·天，而不是最大推荐剂量60 mg/kg·天。
除了体重10 kg且同时使用EIAEDs的儿童以及体重50 kg且未使用EIAEDs的儿童外，该奥卡西平群体药代动力学模型支持当前的剂量推荐。
