Pharmacokinetics of IL-18 binding protein in healthy volunteers and subjects with rheumatoid arthritis or plaque psoriasis

Abstract

IL-18 binding protein (BP) neutralizes the activity of IL-18, a cytokine implicated in psoriasis and rheumatoid arthritis (RA). We investigated the pharmacokinetics, pharmacodynamics and safety of recombinant human IL-18 BP (r-hIL-18 BP) in healthy volunteers and subjects with psoriasis or RA in four phase I studies. A) Healthy volunteers (n = 24) were randomised to receive a single subcutaneous (sc) injection of r-hIL-18 BP (20, 70, 210 or 350 mg) or placebo. B) Healthy volunteers (n = 10) were randomised to receive six sc injections of r-hIL-18 BP (35 or 175 mg, 48 h between injections) or placebo. C) Subjects with moderate-to-severe plaque psoriasis (n = 35) were randomised to receive r-hIL-18 BP (20, 160 or 320 mg, sc tiw) or placebo for 6 weeks. D) Subjects with active, moderate-to-severe RA (n = 36) were randomised to receive r-hIL-18 BP (20, 80, 160 mg, sc tiw) or placebo for 6 weeks. Pharmacokinetics, pharmacodynamics and safety were assessed in all four studies. r-hIL-18 BP showed a dose-dependent pharmacokinetic profile, with a peak serum concentration of 6-48 hours. With repeated sc injections tiw, a steady state was achieved in 1-2 weeks among subjects with psoriasis or RA. The majority of adverse events were mild or moderate in severity. Injection site reactions were the most frequently reported event in subjects with psoriasis or RA. r-hIL-18 BP displays dose-dependent pharmacokinetics, has a favourable safety profile and is well-tolerated in healthy volunteers and in subjects with moderate-to-severe plaque psoriasis or active, moderate-to-severe RA.

Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders

“…This may likely explain the variable success of anti-TNF-a treatment with etanercept, infliximab or adalimumab in different HLH patients [143][144][145][146]. Recombinant human IL-18BP was proven safe in trials with healthy volunteers and patients with rheumatoid arthritis or psoriasis, but so far it has not been tested in HLH [147].…”

Evidence that cytokines play a role in rheumatoid arthritis

“…43), its blockade in rodent models of RA using neutralizing antibody or IL-18-binding protein delivery (a soluble IL-18R that blocks IL-18 function) is effective, and IL-18-deficient mice exhibit ameliorated CIA (44,45). IL-18 is currently being targeted in phase I clinical trials (46). Recently, interest has arisen in IL-32 (originally known as NK4), which was discovered as an IL-18-inducible inflammatory cytokine in epithelial tissues (47).…”

Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure

“…Although still in the initial phases, trials investigating the safety and efficacy of the recombinant human IL-18BP (r-hIL-18BP) and of a blocking IL-18 antibody have been designed over the past years (88)(89)(90). The r-hIL-18BP can be given as a short acting subcutaneous injection and must be given every 2 d to maintain blood levels (89).…”

“…The r-hIL-18BP can be given as a short acting subcutaneous injection and must be given every 2 d to maintain blood levels (89). In healthy volunteers and patients with moderate-to-severe rheumatoid arthritis (RA) or plaque psoriasis, r-hIL-18BP showed favorable safety profiles with adverse events mild to moderate in severity and most commonly including injection site reactions (89). When given every 2 d, steady state levels of r-hIL-18BP were achieved within 4 to 6 d with the half-life of the molecule between 33.7 and 40.1 h (89).…”