ABT-122，一种针对 TNF-α 和 IL-17A 的双可变域免疫球蛋白，在健康受试者和类风湿关节炎患者中的药代动力学：三项 I 期临床试验结果。

Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-Targeted Dual-Variable Domain Immunoglobulin, in Healthy Subjects and Patients with Rheumatoid Arthritis: Results from Three Phase I Trials.

机构信息

AbbVie Inc, 1 North Waukegan Road, North Chicago, IL, 60064, USA.

出版信息

Clin Pharmacokinet. 2018 May;57(5):613-623. doi: 10.1007/s40262-017-0580-y.

DOI:10.1007/s40262-017-0580-y

PMID:28744796

Abstract

BACKGROUND AND OBJECTIVE

ABT-122 is a dual-variable domain immunoglobulin that neutralizes both tumor necrosis factor-α and interleukin-17A, with the goal of achieving greater clinical efficacy than can be achieved by blocking either cytokine alone. This work characterized the pharmacokinetics of ABT-122 in healthy subjects and in patients with rheumatoid arthritis.

METHODS

ABT-122 pharmacokinetics was evaluated in three phase I studies. In Study 1, single intravenous (0.1, 0.3, 1, 3, and 10 mg/kg) and subcutaneous (0.3, 1, and 3 mg/kg) doses were evaluated in healthy subjects. In Studies 2 and 3, multiple subcutaneous doses (1 mg/kg every other week or 0.5-3 mg/kg every week) were evaluated for 8 weeks in patients with rheumatoid arthritis on stable methotrexate therapy. Pharmacokinetic data were available from 48 healthy subjects and 31 patients with rheumatoid arthritis.

RESULTS

ABT-122 showed multi-exponential disposition with more than dose-proportional exposures at the 0.1-1 mg/kg doses and approximately dose-proportional exposures at doses ≥1 mg/kg. ABT-122 absolute subcutaneous bioavailability was approximately 50% with maximum serum concentrations observed 3-4 days after dosing. Steady state was achieved by week 6 of subcutaneous dosing. ABT-122 maximum serum concentration-to-trough concentration ratio was 2.6 for every other week dosing and 1.3 for every week dosing, corresponding to an effective half-life of 10-18 days. ABT-122 median area under the serum concentration-time curve accumulation ratio was 3.8-4.8 with every week dosing. Measureable antidrug antibodies were observed in all 48 subjects in Study 1 by day 15 post-dose and 19 of 31 ABT-122-treated patients in Studies 2 and 3 [median time to appearance of antidrug antibodies of 64 days (range 15-92 days)]. No dose-limiting toxicities were observed in these studies and the maximum tolerated dose was not identified.

CONCLUSIONS

Results from these three phase I studies supported testing ABT-122 every week and every other week regimens in phase II trials in subjects with rheumatoid and psoriatic arthritis. Study 2 (EudraCT: 2012-003448-54); Study 3 (NCT01853033).

摘要

背景与目的

ABT-122 是一种双可变域免疫球蛋白，可中和肿瘤坏死因子-α和白细胞介素-17A，其目标是实现比单独阻断任何一种细胞因子更大的临床疗效。本研究旨在描述 ABT-122 在健康受试者和类风湿关节炎患者中的药代动力学特征。

方法

在三项 I 期研究中评估了 ABT-122 的药代动力学。在研究 1 中，对健康受试者进行了单次静脉（0.1、0.3、1、3 和 10mg/kg）和皮下（0.3、1 和 3mg/kg）剂量的评估。在研究 2 和 3 中，在接受稳定甲氨蝶呤治疗的类风湿关节炎患者中，每两周皮下注射一次 1mg/kg 或每周皮下注射 0.5-3mg/kg，评估了 8 周的 ABT-122 多次皮下给药方案。来自 48 名健康受试者和 31 名类风湿关节炎患者的药代动力学数据可用。

结果

ABT-122 表现出多指数分布，在 0.1-1mg/kg 剂量下呈现出超过剂量比例的暴露，在剂量≥1mg/kg 时呈现出近似剂量比例的暴露。ABT-122 的绝对皮下生物利用度约为 50%，最大血清浓度在给药后 3-4 天出现。皮下给药 6 周时达到稳态。每两周给药时，ABT-122 最大血清浓度-谷浓度比为 2.6，每周给药时为 1.3，对应的有效半衰期为 10-18 天。每周给药时，ABT-122 中位数血清浓度-时间曲线下面积蓄积比为 3.8-4.8。在研究 1 中，所有 48 名受试者在给药后 15 天，以及研究 2 和 3 中的 31 名 ABT-122 治疗患者中的 19 名（出现抗药物抗体的中位数时间为 64 天[范围 15-92 天]），可测量到抗药物抗体。在这些研究中未观察到剂量限制性毒性，也未确定最大耐受剂量。