Abstract：
OBJECTIVE: Vigabatrin is an antiepileptic drug used to treat some forms of severe epilepsy in children. The main adverse effect is ocular toxicity, which is related to the cumulative dose. The aim of the study is to identify an acceptable exposure range, both through the development of a population pharmacokinetic model of vigabatrin in children enabling us to calculate patient exposure and through the study of therapeutic response.
METHODS: We performed a retrospective study including children with epilepsy followed at Necker-Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed-effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range.
RESULTS: We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3-18). A 2-compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC0-24 between 264 and 549 mg.h.L-1.
CONCLUSIONS: The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients.
METHODS: We performed a retrospective study including children with epilepsy followed at Necker-Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed-effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range.
RESULTS: We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3-18). A 2-compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC0-24 between 264 and 549 mg.h.L-1.
CONCLUSIONS: The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients.
摘要：
目的：Vigabatrin是一种抗癫痫药物，用于治疗儿童某些形式的严重癫痫。主要不良反应为眼部毒性,这与累积剂量有关。这项研究的目的是确定一个可接受的暴露范围，通过开发儿童vigabatrin的群体药代动力学模型，使我们能够计算患者的暴露量，并通过研究治疗反应。
方法：我们进行了一项回顾性研究，包括在2019年1月至2022年1月期间在Necker-EnfantsMalades医院接受vigabatrin检测的癫痫患儿。使用非线性混合效应建模方法在Monolix2021上进行了群体药代动力学研究。根据痉挛是否消退，将接受癫痫痉挛治疗的儿童分为有反应者和无反应者组，以确定有效的等离子体暴露范围。
结果：我们纳入了79名患者，分析了159个样本。中位年龄为4.2岁（范围0.3-18）。具有异速率和肌酐清除率的2室模型最符合我们的数据。对61例癫痫性痉挛患者进行暴露分析。有反应的22名患者（36%）中，95%的AUC0-24在264和549mg.h.L-1之间。
结论：群体药代动力学模型使我们能够确定体重和肌酐清除率是解释观察到的vigabatrin个体间差异的2个主要因素。在本研究中定义了可接受的暴露范围。使用此药代动力学模型的目标浓度干预方法可用于避免响应者患者的过度暴露。
方法：我们进行了一项回顾性研究，包括在2019年1月至2022年1月期间在Necker-EnfantsMalades医院接受vigabatrin检测的癫痫患儿。使用非线性混合效应建模方法在Monolix2021上进行了群体药代动力学研究。根据痉挛是否消退，将接受癫痫痉挛治疗的儿童分为有反应者和无反应者组，以确定有效的等离子体暴露范围。
结果：我们纳入了79名患者，分析了159个样本。中位年龄为4.2岁（范围0.3-18）。具有异速率和肌酐清除率的2室模型最符合我们的数据。对61例癫痫性痉挛患者进行暴露分析。有反应的22名患者（36%）中，95%的AUC0-24在264和549mg.h.L-1之间。
结论：群体药代动力学模型使我们能够确定体重和肌酐清除率是解释观察到的vigabatrin个体间差异的2个主要因素。在本研究中定义了可接受的暴露范围。使用此药代动力学模型的目标浓度干预方法可用于避免响应者患者的过度暴露。
