Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis
Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis
复制标题
DOI：
10.1007/s00228-009-0718-4
复制
发表时间：
2009-12-01
影响因子：
2.9
通讯作者：
Zhou, Honghui
中科院分区：
文献类型：
--
作者：
Fasanmade, Adedigbo A.;Adedokun, Omoniyi J.;Zhou, Honghui
英夫利昔单抗是一种单抗，被批准用于治疗炎症性疾病，剂量取决于患者的疾病人口。本研究的目的是评估其在中至重度活动期溃疡性结肠炎患者中的群体药代动力学，并表征影响其在该人群中处置的患者协变量。在两项随机、双盲、安慰剂对照的国际研究中收集的482名患者的信息使用NONMEM进行分析。一个两室群体药代动力学模型描述了英夫利昔单抗的血药浓度-时间数据。根据最终的协变量模型，群体药代动力学估计值(典型值+/-标准误差)为：清除(CL：0.407+/-0.0103 L/天)、中央(V-1：3.29+/-0.0679 L)和外周(V-2：4.13+/-0.16 L)室的表观分布体积，以及室间清除(Q：7.14+/-0.489 L/天)。英夫利昔单抗对CL和V-1的个体间变异分别为37.7%和22.1%。英夫利昔单抗t(1/2)约为14天。协变量分析显示，V-1随着体重的增加而增加，而产生英夫利昔单抗抗体的患者的CL更高。另一个新的协变量，血清白蛋白浓度，被发现与英夫利昔单抗在该人群中的清除率呈负相关。与类风湿性关节炎不同，英夫利昔单抗在中到重度活动性结肠炎患者中的处置不受免疫调节剂和皮质类固醇联合应用的影响，但与英夫利昔单抗抗体的形成有关，特别是与血清白蛋白水平有关。
Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population.Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM.A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value +/- standard error), based on the final covariate model, were clearance (CL: 0.407 +/- 0.0103 L/day), apparent volumes of distribution in the central (V-1: 3.29 +/- 0.0679 L) and peripheral (V-2: 4.13 +/- 0.16 L) compartments, and intercompartment clearance (Q: 7.14 +/- 0.489 L/day). Infliximab exhibited interindividual variability for CL and V-1 of 37.7% and 22.1%, respectively. Infliximab t(1/2) is approximately 14 days. Covariate analysis showed that V-1 increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population.The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels.