Silva Rui, Colom Helena, Bicker Joana, Almeida Anabela, Silva Ana, Sales Francisco, Santana Isabel, Falcão Amílcar, Fortuna Ana
Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
CIBIT/ICNAS-Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal.
Pharmaceutics. 2023 Jun 10;15(6):1704. doi: 10.3390/pharmaceutics15061704.
Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy.
吡仑帕奈因其创新的作用机制，是一种用于治疗难治性癫痫的有前景的抗癫痫药物（AED）。本研究旨在建立一个群体药代动力学（PopPK）模型，以进一步用于诊断为难治性癫痫患者的吡仑帕奈初始剂量优化。通过非线性混合效应建模（NONMEM），采用群体药代动力学方法分析了从44例患者获得的总共72份吡仑帕奈血浆浓度。具有一级消除的单室模型最能描述吡仑帕奈的药代动力学特征。患者间变异性（IPV）针对清除率（CL）输入，而残余误差（RE）建模为成比例。发现酶诱导性抗癫痫药物（EIAEDs）的存在和体重指数（BMI）分别是CL和分布容积（V）的显著协变量。最终模型的CL和V的平均（相对标准误差）估计值分别为0.419 L/h（5.56%）和29.50（6.41%）。IPV为30.84%，成比例RE为6.44%。内部验证表明最终模型具有可接受的预测性能。成功建立了一个可靠的群体药代动力学模型，这是首个纳入诊断为难治性癫痫的成年患者的模型。
