Kovalenko Pavel, Harnisch Lutz, Mendell Jeanne, Wang Yuhuan, Davis John D, DiCioccio Albert Thomas
Research & Preclinical Development (R&PD), Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
Clin Pharmacol Drug Dev. 2025 May;14(5):347-359. doi: 10.1002/cpdd.1523. Epub 2025 Mar 26.
A population pharmacokinetic (PK) covariate analysis was conducted utilizing data from adolescents and children ≥8 to <12 years of age with heterozygous familial hypercholesterolemia. One phase II and 1 phase III study were analyzed (121 patients on active treatment). A 2-compartment target-mediated model with linear and target-mediated elimination and transit compartments describing lag time in absorption was utilized. Weight and high-dose statins were statistically significant covariate. Except for the central volume, estimated population PK parameters describing linear kinetics were similar across pediatric patients and healthy adults. Coadministration of concomitant high doses of statins was associated with an increase in the production rate of proprotein convertase subtilisin/kexin type 9. The primary covariate model adequately described alirocumab PKs in the pediatric population. The analysis supports the recommended weight-adjusted subcutaneous dosing regimens for alirocumab in children with heterozygous hypercholesterolemia aged ≥8 years.
利用来自8至<12岁杂合子家族性高胆固醇血症青少年和儿童的数据进行了群体药代动力学（PK）协变量分析。分析了1项II期和1项III期研究（121例接受活性治疗的患者）。使用了一个具有线性和靶点介导消除以及描述吸收滞后时间的转运室的二室靶点介导模型。体重和高剂量他汀类药物是具有统计学意义的协变量。除中央室容积外，描述线性动力学的估计群体PK参数在儿科患者和健康成年人中相似。同时给予高剂量他汀类药物与前蛋白转化酶枯草杆菌蛋白酶/kexin 9型的产生率增加有关。主要协变量模型充分描述了alirocumab在儿科人群中的PK。该分析支持了针对≥8岁杂合子高胆固醇血症儿童使用alirocumab时推荐的体重调整皮下给药方案。
