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
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.
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.
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.
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)
The authors thank Allison Kitten, PhD, an employee of AbbVie, for medical writing support.
Compliance with Ethical Standards
The studies were sponsored by AbbVie. AbbVie contributed to the study designs, research, and interpretation of data, and the writing, review, and approval of the publication.
Conflict of interest
Amit Khatri, Sandra Goss, Ping Jiang, Heikki Mansikka, and Ahmed A. Othman are employees of AbbVie and may hold AbbVie stock or stock options.
The studies were conducted in accordance with Good Clinical Practice guidelines and the ethical principles that have their origin in the Declaration of Helsinki. The protocols and informed consent forms were approved by the institutional review boards at each site.
Consent to participate
All participants provided written informed consent before any study-related procedures were performed.
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