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Pharmacokinetics and Tolerability of a Dual Variable Domain Immunoglobulin ABT‐981 Against IL‐1α and IL‐1β in Healthy Subjects and Patients With Osteoarthritis of the Knee
Author(s) -
Kosloski Matthew P.,
Goss Sandra,
Wang Susanne X.,
Liu Jia,
Loebbert Ralf,
Medema Jeroen K.,
Liu Wei,
Dutta Sandeep
Publication year - 2016
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.764
Subject(s) - medicine , osteoarthritis , tolerability , pharmacokinetics , placebo , synovial fluid , proinflammatory cytokine , gastroenterology , adverse effect , immunology , pathology , inflammation , alternative medicine
The interleukin (IL)‐1 family of proinflammatory cytokines are thought to play a significant role in the structural progression of osteoarthritis and its associated symptoms. IL‐1α and IL‐1β are 2 distinct cytokines found in the cartilage, synovial membrane, and synovial fluid of patients with osteoarthritis. The aim of these studies was to evaluate the pharmacokinetics of ABT‐981, a dual variable domain immunoglobulin (DVD‐Ig) capable of simultaneously binding IL‐1α and IL‐1β, in healthy subjects and patients with osteoarthritis of the knee. Fifty‐six healthy adult subjects were randomized to receive single doses of ABT‐981 intravenously (0.3, 1, 3, or 10 mg/kg), subcutaneously (0.3, 1, 3 mg/kg), or matching placebo in a 3:1 ratio. Thirty‐six patients with osteoarthritis of the knee were randomized to receive 4 subcutaneous ABT‐981 doses of 0.3, 1, or 3 mg/kg administered every 2 weeks, 3 subcutaneous doses of ABT‐981 3 mg/kg every 4 weeks, or matching placebo in a 7:2 active:placebo ratio. ABT‐981 behaved similarly to conventional monoclonal antibodies following single or multiple doses with mean maximum serum concentrations 2 to 9 days after subcutaneous doses, mean terminal half‐lives of 10 to 14 days, and an absolute subcutaneous bioavailability of 46%. Exposure of ABT‐981 was approximately linear following single or multiple doses every 2 weeks with monoexponential decline of terminal‐phase concentrations. The most common adverse events associated with ABT‐981 were diarrhea and headache in healthy subjects and injection site erythema in subjects with osteoarthritis of the knee. Decreased absolute neutrophil counts were observed in response to ABT‐981 administration.