Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials
Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials
复制标题
DOI：
10.1016/j.clinthera.2011.06.002
复制
发表时间：
2011-07-01
影响因子：
3.2
通讯作者：
Davis, Hugh M.
中科院分区：
文献类型：
--
作者：
Fasanmade, Adedigbo A.;Adedokun, Omoniyi J.;Davis, Hugh M.
背景：英夫利昔单抗是一种针对 TNF α 的嵌合单克隆抗体。英夫利昔单抗的药代动力学 (PK) 特性已在多个成年患者群体中进行了研究，但文献检索未发现该药物在儿科患者中的比较群体 PK 特性的报道。 目标：当前分析应用群体 PK 技术来比较来自 2 项 III 期研究的中度至重度活动性克罗恩病 (CD) 儿童和成人患者中英夫利昔单抗的 PK 特性数据。方法：该分析使用了 692 名患者的血清英夫利昔单抗浓度数据（112 名儿童，580 名成人；年龄范围为 6-76 岁）来自 2 项 III 期临床研究（REACH [一项随机、多中心、开放标签研究，旨在评估抗 TNF-α 嵌合单克隆抗体在中度至重度克罗恩病儿童受试者中的安全性和有效性] 和 ACCENT I [一项在新的、评估英夫利昔单抗的克罗恩病临床试验、长期治疗方案]）。 PK 模型是针对儿童、成人以及两者的组合单独开发的。组合群体用于在组合 CD 群体中建立英夫利昔单抗 PK 特性的重要协变量。使用组合 PK 和协变量数据进行探索性模拟，以扩大对儿童结果的解释。结果：根据研究结果，在正在接受英夫利昔单抗和免疫调节剂治疗的典型儿童（根据 REACH 中值，体重 42 kg，基线血清白蛋白浓度 [SAC] 3.8 mg/dL，并且尚未产生英夫利昔单抗 [ATI] 抗体）中，PK 估计值（典型值 [SE]）如下：清除率（CL），5.43（0.15）mL/kg/d；中央室 (V-1) 中的 V-d，54.2 (1.15) mL/kg；外周室 (V-2) 中的 V-d，29.2 (2.03) mL/kg；室间隙 (Q) 为 3.52 (0.71) mL/kg/d。典型成人（体重，68 kg；SAC，4.1 mg/dL）的相应特性为 CL，5.39 (0.13) mL/kg/d； V-1，52.7（0.49）毫升/千克； V-2，19.0 (1.53) 英里/公斤； Q，2.15 (0.39) mL/kg/d。 V-2 随着体重增加而下降，预测体重较低的个体可能对每公斤体重英夫利昔单抗剂量的暴露补偿不足。在儿童和成人患者中，患有 ATI 或基线 SAC 较低的患者的 CL 较高。同时使用免疫调节剂（嘌呤抗代谢药或甲氨蝶呤）与 CL 降低 14% 相关。在儿科和成人患者中，观察到的英夫利昔单抗血清谷浓度、中位英夫利昔单抗 t(1/2)（儿童为 13.2 天；成人为 12.4 天）以及探索性 PK 模拟预测英夫利昔单抗 PK 特性在儿童和成人之间具有可比性。结论：英夫利昔单抗 PK 特性在儿科和成人 CD 患者之间似乎具有可比性。具体而言，在使用非线性混合效应模型的选定人群中，英夫利昔单抗 CL 随着 SAC 降低而增加。 CL 也随着 ATI 的形成而增加，但随着免疫调节剂的共同给药而减少。尽管体重影响英夫利昔单抗 PK 特性（总 CL 和总 Vd 随总体重增加，而每公斤 CL 和 Vd 随总体重减少），但在测试的年龄范围（6-76 岁）中，未发现年龄影响英夫利昔单抗 PK。 (Clin Ther. 2011;33:946-964) (C) 2011 Elsevier HS Journals, Inc. 保留所有权利。
Background: Infliximab is a chimeric monoclonal antibody against TNF alpha. The pharmacokinetic (PK) properties of infliximab have been studied in several adult patient populations, but a literature search identified no reported comparative population PK properties of this drug in pediatric patients.Objectives: The current analysis applied population PK techniques to compare data on the PK properties of infliximab in pediatric and adult patients with moderately to severely active Crohn's disease (CD) from 2 Phase III studies.Methods: This analysis used serum infliximab concentration data from 692 patients (112 children, 580 adults; age range, 6-76 years) from 2 Phase III clinical studies (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-alpha Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohn's Disease] and ACCENT I [A Crohn's Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]). PK models were developed separately for children, adults, and a combination of both. The combined population was used for establishing important covariates of infliximab PK properties in the combined CD population. Exploratory simulations using combined PK and covariate data were performed to expand the interpretation of the results in children.Results: Based on the findings, in a typical child (who, based on the median values in REACH, weighs 42 kg, has a baseline serum albumin concentration [SAC] 3.8 mg/dL, and has not developed antibodies to infliximab [ATIs]) who is receiving infliximab and an immunomodulator, PK estimates (typical value [SE]) were as follows: clearance (CL), 5.43 (0.15) mL/kg/d; V-d in the central compartment (V-1), 54.2 (1.15) mL/kg; V-d in the peripheral compartment (V-2), 29.2 (2.03) mL/kg; and intercompartmental clearance (Q), 3.52 (0.71) mL/kg/d. Corresponding properties in a typical adult (weight, 68 kg; SAC, 4.1 mg/dL) were CL, 5.39 (0.13) mL/kg/d; V-1, 52.7 (0.49) mL/kg; V-2, 19.0 (1.53) mi./kg; and Q, 2.15 (0.39) mL/kg/d. V-2 decreased as body weight increased, predicting a possible undercompensation for exposure with infliximab dosing per kg weight in lower-weight individuals. In pediatric and adult patients, CL was higher in those in whom ATIs developed or who had low baseline SAC. Concurrent immunomodulator use (purine antimetabolites or methotrexate) was associated with a 14% decrease in CL. In the pediatric and adult patients, observed trough serum infliximab concentrations, median infliximab t(1/2) (in children, 13.2 days; and in adults, 12.4 days), and exploratory PK simulations predicted infliximab PK properties to be comparable between children and adults.Conclusions: Infliximab PK properties appeared to be comparable between pediatric and adult patients with CD. Specifically, in this select population using nonlinear mixed effects modeling, infliximab CL increased as SAC decreased. CL also increased with ATI formation but decreased with immunomodulator co-administration. Although weight affects infliximab PK properties (total CL and total Vd increased with total body weight while per kg CL and Vd decrease with total body weight), age was not found to influence infliximab PK in the age range tested (6-76 years). (Clin Ther. 2011;33:946-964) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.