title: 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.
abstract: 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.
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Kosloski
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Goss
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Susanne X
authors.initials: SX
authors.lastname: Wang
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: AbbVie Deutschland GmbH and Co KG, Wiesbaden, Hesse, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Loebbert
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Jeroen K
authors.initials: JK
authors.lastname: Medema
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000378:metabolism*; D007135:Immunoglobulin Variable Region / Q000008:administration & dosage / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D053582:Interleukin-1alpha; D053583:Interleukin-1beta
keywords: ABT-981; interleukin-1α; interleukin-1β; osteoarthritis; pharmacokinetics