Karatza Eleni, Markantonis Sophia L, Savvidou Andria, Verentzioti Anastasia, Siatouni Anna, Alexoudi Athanasia, Gatzonis Stylianos, Mavrokefalou Evgenia, Karalis Vangelis
Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece.
Department of Neurosurgery, Evangelismos Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Xenobiotica. 2020 Sep;50(9):1090-1100. doi: 10.1080/00498254.2020.1746981. Epub 2020 Apr 7.
This study aimed to evaluate the pharmacokinetics and pharmacodynamics of oral levetiracetam therapy in drug refractory adult epileptic outpatients, as well as factors affecting them. Concentration-time data were collected at steady state, while seizure recurrence was monitored for 13 months. Non-linear mixed effects modeling was applied, and covariates assessed included weight, height, age, daily dose and creatinine clearance.Plasma concentrations of levetiracetam were best described by a one-compartment pharmacokinetic model (/ = 34.7 L) with first-order absorption (ka = 0.616 h) and clearance (CL/ = 3.26 L/h). Patient's CrCL was found to significantly affect levetiracetam clearance (beta = 0.795). Time to seizure occurrence followed an exponential distribution and the mean time to seizure occurrence was estimated Te = 22.08 days. Seizure rate per month followed a Poisson distribution, while mean seizure rate per month was estimated = 1.33. Daily dose significantly affected the mean estimated time to seizure (beta = -2.2) and the mean monthly seizure rate (beta = 2.27) in a reverse way. Using discrete time Markov chains, it was shown that the transition probability from focal seizures to focal to bilateral tonic-clonic is significantly altered in relation to patient's CrCL.Simulations showed that dose should be adjusted in relation to CrCL, while low doses of levetiracetam are more effective for seizure control. Modeling and simulation in every-day clinical practice may provide significant information for the optimization of seizure control using well-known agents.
本研究旨在评估口服左乙拉西坦治疗药物难治性成年癫痫门诊患者的药代动力学和药效学，以及影响它们的因素。在稳态时收集浓度-时间数据，同时监测癫痫复发情况13个月。应用非线性混合效应模型，评估的协变量包括体重、身高、年龄、每日剂量和肌酐清除率。左乙拉西坦的血浆浓度最好用具有一级吸收（ka = 0.616 h）和清除率（CL/ = 3.26 L/h）的单室药代动力学模型（/ = 34.7 L）来描述。发现患者的肌酐清除率显著影响左乙拉西坦的清除率（β = 0.795）。癫痫发作时间呈指数分布，估计癫痫发作的平均时间Te = 22.08天。每月癫痫发作率呈泊松分布，而估计每月平均癫痫发作率 = 1.33。每日剂量以相反的方式显著影响癫痫发作的平均估计时间（β = -2.2）和每月平均癫痫发作率（β = 2.27）。使用离散时间马尔可夫链表明，与患者的肌酐清除率相关，从局灶性癫痫发作到局灶性至双侧强直阵挛性癫痫发作的转变概率有显著改变。模拟表明，应根据肌酐清除率调整剂量，而低剂量的左乙拉西坦对癫痫控制更有效。在日常临床实践中进行建模和模拟可为使用知名药物优化癫痫控制提供重要信息。
