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Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis

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Author: Zuurmond, A.M. · Koudijs, A. · El, B. van · Doornbos, R.P. · Manen-Vernooij, B.C.T. van · Bastiaans, J.H.M.W. · Penninks, A.H. · Bilsen, J.H.M. van · Cnubben, N.H.P. · Groot, J. de
Type:article
Date:2011
Source:Regulatory Toxicology and Pharmacology, 3, 59, 461-470
Identifier: 428335
doi: doi:10.1016/j.yrtph.2011.01.014
Keywords: Nutrition · Anakinra · Biologics · Cytokines · IL-1 receptor antagonist · Immunotoxicity · Inflammation · Joint degradation markers · Pharmacokinetics · Rat adjuvant arthritis · Rheumatoid arthritis · Life Triskelion BV · MHR - Metabolic Health Research TAP - Toxicology and Applied Pharmacology QS - Quality & Safety PHS - Pharmacokinetics & Human Studies · EELS - Earth, Environmental and Life Sciences

Abstract

Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in Cmax and an increase of the MRT as the disease progressed at a dose of 24 and 72mgAnakinra/kgbody weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure. © 2011 Elsevier Inc.