E2Bio Consultants, 2906 Central St, Evanston, IL, 60201, USA.
Drugs R D. 2017 Dec;17(4):607-613. doi: 10.1007/s40268-017-0211-y.
Infliximab pharmacokinetic studies have been performed in patients receiving chronic infliximab therapy. In these patients, infliximab antidrug antibodies (ADAs) increase infliximab clearance and decrease serum levels and drug efficacy.
This study analyzed the pharmacokinetic effect of infliximab ADAs in healthy subjects receiving a single dose of intravenous infliximab.
Data were obtained from a single-blind, parallel-group, single-dose study of healthy subjects receiving 5 mg/kg of intravenous SB2 (infliximab biosimilar), EU-sourced Remicade (EU-IFX) or US-sourced Remicade (US-IFX). Serum infliximab was measured at 1, 2, 3, 6, 12, 24, 48, and 72 h and at 5, 7, 14, 21, 28, 42, 56, and 70 days after administration. ADAs were measured pre-dose and at 29 and 71 days. Data from the first ten subjects randomized to each treatment arm were utilized for this study. A two-compartment model of the serum infliximab vs. time curve was developed using nonlinear regression.
At 10 weeks, 11 subjects (37%) developed ADAs. ADAs were detected in four subjects after SB2, one subject after EU-IFX, and six subjects after US-IFX infusion. Of these, neutralizing antibodies occurred in one subject after SB2, in no subjects after EU-IFX, and in three subjects after US-IFX infusion. Infliximab clearance was increased in subjects with ADAs vs. those without ADAs (12.89 ± 2.69 vs. 9.90 ± 1.74 ml/h; p < 0.0005). The elimination half-time was shorter in subjects with ADAs (282.4 ± 56.4 vs. 343.3 ± 61.9 h; p < 0.01). Serum infliximab measured at 8 weeks correlated closely with infliximab clearance (R = 0.5494; p < 0.0001).
ADAs are common in healthy subjects after a single intravenous dose of infliximab and result in faster infliximab clearance, shorter elimination time, and lower serum infliximab levels. These data confirm that ADAs are common with biologic therapy and significantly impact the efficacy of these drugs.
已有研究对接受英夫利昔单抗（IFX）长期治疗的患者进行了英夫利昔单抗药代动力学研究。这些患者体内的英夫利昔单抗抗药物抗体（ADA）会增加英夫利昔单抗清除率，降低血清水平和药物疗效。
本研究旨在分析健康受试者单次静脉输注英夫利昔单抗时，英夫利昔单抗 ADA 对药代动力学的影响。
本研究为单盲、平行分组、单次剂量研究，纳入了健康受试者，受试者接受 5mg/kg 静脉注射 SB2（英夫利昔单抗生物类似药）、EU-IFX 或 US-IFX。给药后 1、2、3、6、12、24、48 和 72 小时以及 5、7、14、21、28、42、56 和 70 天，测量血清英夫利昔单抗浓度；给药前和 29 天、71 天测量 ADA。本研究分析了前 10 名随机分配至各治疗组的受试者的数据。采用非线性回归分析建立了血清英夫利昔单抗浓度-时间曲线的两室模型。
10 周时，11 名受试者（37%）出现 ADA。SB2 组有 4 名、EU-IFX 组有 1 名、US-IFX 组有 6 名受试者出现 ADA。其中，SB2 组有 1 名出现中和性 ADA，EU-IFX 组和 US-IFX 组均未出现中和性 ADA，US-IFX 组有 3 名出现非中和性 ADA。ADA 阳性组的英夫利昔单抗清除率高于 ADA 阴性组（12.89±2.69ml/h vs. 9.90±1.74ml/h；p<0.0005）。ADA 阳性组的英夫利昔单抗消除半衰期较短（282.4±56.4h vs. 343.3±61.9h；p<0.01）。8 周时的血清英夫利昔单抗浓度与英夫利昔单抗清除率密切相关（R=0.5494；p<0.0001）。
健康受试者单次静脉输注英夫利昔单抗后，ADA 较为常见，会导致英夫利昔单抗清除率加快、消除时间缩短、血清英夫利昔单抗水平降低。这些数据证实，ADA 是生物治疗中常见的现象，会显著影响这些药物的疗效。
