Wang Yang, Zhang Hua-nian, Niu Chang-he, Gao Ping, Chen Yu-jun, Peng Jing, Liu Mao-chang, Xu Hua
Department of Pharmacy, Wuhan Children's Hospital, 100th-Hong Kong Road, Wuhan 430016, China.
Acta Pharmacol Sin. 2014 Oct;35(10):1342-50. doi: 10.1038/aps.2014.76. Epub 2014 Sep 15.
To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs (AEDs).
A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model (n=573) and valid (n=115) groups. Serum concentrations of the main active metabolite of oxcarbazepine, 10-hydroxycarbazepine (MHD), were determined 0.5-48 h after the last dosage. A population pharmacokinetics (PPK) model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error (MPE), mean absolute prediction error (MAE), mean squared prediction error (MSE) and the 95% confidence intervals (95% CI) to externally evaluate the model.
The population values of pharmacokinetic parameters estimated in the final model were as follows: Ka=0.83 h-1, Vd=0.67 L/kg, and CL=0.035 L·kg(-1)·h(-1). The enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) and newer generation AEDs (levetiracetam, lamotrigine, topiramate) increased the weight-normalized CL value of MHD by 17.4% and 10.5%, respectively, whereas the enzyme-inhibiting AED valproic acid decreased it by 3%. No significant association was found between the CL value of MHD and the other covariates. For the final model, the evaluation results (95% CI) were MPE=0.01 (-0.07-0.10) mg/L, MAE=0.46 (0.40-0.51) mg/L, MSE=0.39 (0.27-0.51) (mg/L)(2).
A PPK model of OXC in Chinese pediatric patients with epilepsy is established. The enzyme-inducing AEDs and some newer generation AEDs (lamotrigine, topiramate) could slightly increase the metabolism of MHD.
建立中国癫痫患儿奥卡西平的群体药代动力学模型，并研究奥卡西平与其他抗癫痫药物（AEDs）之间的相互作用。
将688例年龄在2个月至18岁的癫痫患者分为建模组（n = 573）和验证组（n = 115）。在末次给药后0.5 - 48小时测定奥卡西平主要活性代谢物10 - 羟基卡马西平（MHD）的血清浓度。使用非线性混合效应（NLME）软件构建群体药代动力学（PPK）模型。该模型通过自抽样法和拟合优度图检验进行内部评估。使用验证组的数据计算平均预测误差（MPE）、平均绝对预测误差（MAE）、平均平方预测误差（MSE）和95%置信区间（95%CI）以对外评估模型。
最终模型中估算的药代动力学参数群体值如下：Ka = 0.83 h⁻¹，Vd = 0.67 L/kg，CL = 0.035 L·kg⁻¹·h⁻¹。酶诱导性抗癫痫药物（卡马西平、苯妥英、苯巴比妥）和新一代抗癫痫药物（左乙拉西坦、拉莫三嗪、托吡酯）分别使MHD的体重标准化CL值增加17.4%和10.5%，而酶抑制性抗癫痫药物丙戊酸使其降低3%。未发现MHD的CL值与其他协变量之间存在显著关联。对于最终模型，评估结果（95%CI）为MPE = 0.01（-0.07 - 0.10）mg/L，MAE = 0.46（0.40 - 0.51）mg/L，MSE = 0.39（0.27 - 0.51）（mg/L）²。
建立了中国癫痫患儿奥卡西平的PPK模型。酶诱导性抗癫痫药物和一些新一代抗癫痫药物（拉莫三嗪、托吡酯）可轻微增加MHD的代谢。
