Department of Medicine, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Clin Pharmacokinet. 2018 Dec;57(12):1593-1601. doi: 10.1007/s40262-018-0653-6.
Infliximab, a monoclonal antibody directed against tumor necrosis factor-α, is being evaluated as adjunctive therapy to intravenous immunoglobulin (IVIG) for treatment of young children with acute Kawasaki disease (KD).
The aim of this study was to develop a population pharmacokinetic (PopPK) model for infliximab in children with KD, and to evaluate the impact of covariates on infliximab disposition. Specifically, we wanted to investigate the effect of body weight and IVIG administration on PK parameters.
In the current PopPK analysis, 70 subjects with a median (interquartile range) age of 2.9 years (1.3-4.4) were included from two randomized controlled trials. Infliximab concentration-time data were best described by a two-compartment model with first-order elimination using non-linear mixed-effects modeling (NONMEM 7.3).
The clearance, volume of distribution of the central (V1) and peripheral (V2) compartment, and intercompartmental clearance estimates (95% confidence interval) from the PopPK analysis were 0.117 (0.091-0.134) L/day, 0.801 (0.545-0.960) L, 0.962 (0.733-1.759) L, and 0.692 (0.482-1.779) L/day, respectively. Allometric body weight was included on all parameters of the structural model and a covariate analysis revealed that administering infliximab after IVIG, as opposed to before, resulted in a 50% decrease in V2.
Our study shows that the timing of infliximab administration relative to IVIG administration affects the disposition of the monoclonal antibody. These results may have important implications for other monoclonal antibodies administered in combination with IVIG for treating inflammatory diseases.
英夫利昔单抗是一种针对肿瘤坏死因子-α的单克隆抗体，目前正在评估作为静脉注射免疫球蛋白（IVIG）的辅助治疗药物，用于治疗急性川崎病（KD）的幼儿。
本研究旨在建立川崎病患儿英夫利昔单抗的群体药代动力学（PopPK）模型，并评估协变量对英夫利昔单抗处置的影响。具体而言，我们希望研究体重和 IVIG 给药对 PK 参数的影响。
在当前的 PopPK 分析中，纳入了两项随机对照试验的 70 名中位（四分位间距）年龄为 2.9 岁（1.3-4.4）的患儿。使用非线性混合效应模型（NONMEM 7.3），英夫利昔单抗浓度-时间数据最好用具有一级消除的两室模型来描述。
PopPK 分析中得出的清除率、中央（V1）和外周（V2）分布容积以及隔室间清除率估计值（95%置信区间）分别为 0.117（0.091-0.134）L/天、0.801（0.545-0.960）L、0.962（0.733-1.759）L 和 0.692（0.482-1.779）L/天。所有体型体重均包含在结构模型的所有参数中，协变量分析显示，与 IVIG 给药前相比，IVIG 后给予英夫利昔单抗可使 V2 降低 50%。
本研究表明，英夫利昔单抗相对于 IVIG 给药的给药时间会影响单克隆抗体的处置。这些结果可能对其他与 IVIG 联合用于治疗炎症性疾病的单克隆抗体具有重要意义。
