A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy
A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy
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DOI：
10.1007/s00228-018-2444-2
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发表时间：
2018-06-01
影响因子：
2.9
通讯作者：
Jullien, Vincent
中科院分区：
文献类型：
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作者：
Rodrigues, Christelle;Chhun, Stephanie;Jullien, Vincent
目的：建立丙戊酸（VPA）缓释颗粒剂在癫痫儿童中的群体药代动力学模型，并确定使VPA谷浓度（C-trough）在目标范围（50 - 100 mg/L）内的剂量。方法：98例儿童（1 - 17.6岁，325份血浆样本）纳入本研究。模型使用NONMEM 7.3构建。通过Monte Carlo模拟确定了20、30、40和60 mg/kg/d剂量和10 - 70 kg体重的C谷浓度在50 - 100 mg/L之间的概率。结果采用一室模型描述数据，该模型具有一阶吸收和触发参数化以及线性消除，但考虑了蛋白结合。未结合VPA清除率和分布容积的典型值分别为6.24 L/h/70 kg和130 L/h/70 kg。通过异速生长模型，两个参数均与体重相关。对于10 kg儿童，40 mg/kg日剂量获得目标范围内C谷值的概率最高，而对于20 - 30和>= 40 kg儿童，30和20 mg/kg日剂量分别适用。结论如果本研究支持目前推荐的20 - 30 mg/kg/d的剂量，除了20 kg以下的儿童可能需要更高的剂量外，还需要进一步研究未结合VPA的药代动力学/药效学特征。
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 (C-trough) 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 C-trough 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 C-trough 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.