Skip to main content
SpringerLink
Log in

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

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. 1. De Rie, M.A., Meinardi, M.M. & Bos, J.D. (1990). Analysis of side-effects of medium- and low-dose cyclosporin maintenance therapy in psoriasis.British Journal of Dermatology, 123, 347–353.

    Article  PubMed  Google Scholar 

  2. Whiting-O’Keefe, Q.E., Fye, K.H. & Sack, K.D. (1991). Methotrexate and histologic hepatic abnormalities: a meta-analysis.American Journal of Medicine, 90, 711–716.

    PubMed  Google Scholar 

  3. Caldwell, J.R. & Furst, D.E. (1991). The efficacy and safety of low-dose corticosteroids for rheumatoid arthritis.Seminars in Arthritis and Rheumatism, 21, 1–11.

    Article  CAS  PubMed  Google Scholar 

  4. Bresnihan, B., Roux-Lombard, P., Murphy, E., Kane, D., FitzGerald, O. & Dayer, J.M. (2002). Serum interleukin 18 andinterleukin 18 binding protein in rheumatoid arthritis.Annals of the Rheumatic Diseases, 61, 726–729.

    Article  CAS  PubMed  Google Scholar 

  5. Dinarello, C.A. (2004). Interleukin-18 and the treatment of rheumatoid arthritis.Rheumatic Diseases Clinics of North America, 30, 417–434, ix.

    Article  PubMed  Google Scholar 

  6. Gracie, J.A., Forsey, R.J., Chan, W.L., Gilmour, A., Leung, B.P., Greer, M.R., Kennedy, K., Carter, R., Wei, X.Q., Xu, D., Field, M., Foulis, A., Liew, F.Y. & McInnes, I.B. (1999). A proinflammatory role for IL-18 in rheumatoid arthritis.Journal of Clinical Investigation, 104, 1393–1401.

    Article  CAS  PubMed  Google Scholar 

  7. Gangemi, S., Merendino, R.A., Guameri, F., Minciullo, P.L., DiLorenzo, G., Pacor, M. & Cannavo, S.P. (2003). Serum levels of interleukin-18 and s-ICAM-1 in patients affected by psoriasis: preliminary considerations.Journal of the European Academy of Dermatology and Venereology, 17, 42–16.

    Article  CAS  PubMed  Google Scholar 

  8. Ohta, Y., Hamada, Y. & Katsuoka, K. (2001). Expression of IL-18 in psoriasis.Archives of Dermatological Research, 293, 334–342.

    Article  CAS  PubMed  Google Scholar 

  9. Kohno, K. & Kurimoto, M. (1998). Interleukin 18, a cytokine which resembles IL-1 structurally and IL-12 functionally but exerts its effect independently of both.Clinical Immunology and Immunopathology, 86, 11–15.

    Article  CAS  PubMed  Google Scholar 

  10. Micallef, M.J., Ohtsuki, T., Kohno, K., Tanabe, F., Ushio, S., Namba, M., Tanimoto, T., Torigoe, K., Fujii, M., Ikeda, M., Fukuda, S. & Kurimoto, M. (1996). Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production.European Journal of Immunology, 26, 1647–1651.

    Article  CAS  PubMed  Google Scholar 

  11. Okamura, H., Tsutsui, H., Kashiwamura, S., Yoshimoto, T. & Nakanishi, K. (1998). Interleukin-18: a novel cytokine that augments both innate and acquired immunity.Advances in Immunology, 70, 281–312.

    Article  CAS  PubMed  Google Scholar 

  12. Puren, A.J., Fantuzzi, G., Gu, Y., Su, M.S. & Dinarello, C.A. (1998). Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-lbeta via TNFalpha production from non- CD14+ human blood mononuclear cells.Journal of Clinical Investigation, 101, 711–721.

    Article  CAS  PubMed  Google Scholar 

  13. Ushio, S., Namba, M., Okura, T., Hattori, K., Nukada, Y., Akita, K., Tanabe, F., Konishi, K., Micallef, M., Fujii, M., Torigoe, K., Tanimoto, T., Fukuda, S., Ikeda, M., Okamura, H. & Kurimoto, M. (1996). Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein.Journal of immunology, 156, 4274–4279.

    CAS  Google Scholar 

  14. Okamura, H., Tsutsi, H., Komatsu, T., Yutsudo, M., Hakura, A., Tanimoto, T., Torigoe, K., Okura, T., Nukada, Y., Hattori, K. & et al. (1995). Cloning of a new cytokine that induces IFN-gamma production by T cells.Nature, 378, 88–91.

    Article  CAS  PubMed  Google Scholar 

  15. Takeda, K., Tsutsui, H., Yoshimoto, T., Adachi, O., Yoshida, N., Kishimoto, T., Okamura, H., Nakanishi, K. & Akira, S. (1998). Defective NK cell activity and Th1 response in IL-18-deficient mice.Immunity, 8, 383–390.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, The Netherlands

    Paul P. Tak

  2. Serono International SA, Geneva, Switzerland

    Marisa Bacchi & Mauro Bertolino

Authors
  1. Paul P. Tak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marisa Bacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mauro Bertolino
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

IL-18 BP Study GroupCanada: Professor Robert Bissonnette, Professor Kim Papp, Professor Neil Shear; Croatia: Professor Bozidar Curkovic;Germany: Professor Wolfram Sterry;Serbia and Montenegro: Professor Aleksandar Dimic, Professor Vladimir Mircetic;Slovak Republic: Dr Zlata Kmecova, Professor Josef Ravensky;Slovenia: Professor Blaz Rozman;The Netherlands: Professor Paul Tak;UK: Dr Iain Mclnnes, Dr Anthony Priestley, Dr Amran Saifulanwar, Dr Rene Van der Merwe.

Please send reprint requests to: Andrew Desson, SERONO International S.A. 15 bis, Chemin des Mines, 1202 Geneva, Switzerland

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tak, P.P., Bacchi, M. & Bertolino, M. Pharmacokinetics of IL-18 binding protein in healthy volunteers and subjects with rheumatoid arthritis or plaque psoriasis. European Journal of Drug Metabolism and Pharmacokinetics 31, 109–116 (2006). https://doi.org/10.1007/BF03191127

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03191127

Keywords

Search

Navigation