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 (V/F = 34.7 L) with first-order absorption (ka = 0.616 h⁻¹) and clearance (CL/F = 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 λ = 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.

这项研究旨在评估口服左乙拉西坦治疗难治性成人癫痫患者的药代动力学和药效学，以及影响他们的因素。在稳定状态下收集浓度-时间数据，同时监测癫痫发作的复发情况，持续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，日剂量和肌酐清除率。

左乙拉西坦的血浆浓度最好通过具有一 阶吸收（ka = 0.616 h ^-1）和清除（CL / F  = 3.26 L / h）的单室药代动力学模型（V / F = 34.7 L）来描述。发现患者的CrCL显着影响左乙拉西坦的清除率（β= 0.795）。癫痫发作的时间呈指数分布，估计的平均癫痫发作时间为Te = 22.08天。每月癫痫发作率遵循泊松分布，而每月平均癫痫发作率估计为λ = 1.33。每日剂量以相反的方式显着影响平均估计癫痫发作时间（β= -2.2）和平均每月癫痫发作率（β= 2.27）。使用离散时间马尔可夫链，表明从局灶性癫痫发作到局灶性双侧强直性阵挛的转变概率相对于患者的CrCL显着改变。

模拟表明应相对于CrCL调整剂量，而小剂量的左乙拉西坦更有效控制癫痫发作。日常临床实践中的建模和仿真可以为使用知名药物优化癫痫发作控制提供重要信息。