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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Population Dose-Response Analysis of Daily Seizure Count Following Vigabatrin Therapy in Adult and Pediatric Patients with Refractory Complex Partial Seizures
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Population Dose-Response Analysis of Daily Seizure Count Following Vigabatrin Therapy in Adult and Pediatric Patients with Refractory Complex Partial Seizures

机译：Vigabatrin治疗后成人和小儿难治性复杂性部分发作的每日发作计数的人群剂量反应分析

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摘要

Vigabatrin is an irreversible inhibitor of -aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively.
机译：Vigabatrin是-氨基丁酸转氨酶（GABA-T）的不可逆抑制剂，被用作难治性复杂性部分性发作（rCPS）的成年患者的辅助治疗。这项研究的目的是描述vgabatrin剂量与rCPS成人和儿童每日癫痫发作率之间的关系，并确定可能影响癫痫发作频率的相关协变量。这项人群剂量反应分析使用了来自三名儿科和两项成人rCPS患者随机对照研究的癫痫发作计数数据。负二项分布模型可以充分描述每日的癫痫发作数据。首次给药后平均癫痫发作率随时间降低，并使用渐近模型进行描述。使用标准化剂量作为暴露指标的二次模型可以最好地描述维加巴特林的药物作用。归一化剂量是估计的参数，该参数允许根据体重对vigabatrin的暴露进行个体化改变。基线癫痫发作率随年龄的降低而增加，但在按体重差异归一化剂量后，年龄对vigabatrin药物作用没有影响。后预测检查表明最终模型能够模拟与观察到的每日癫痫发作计数一致的数据。预计每天1、3和6g标准化的维加巴特林总剂量可分别降低癫痫发作率23.2％，45.6％和48.5％。

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