Title
Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis
Author
Zuurmond, A.M.
Koudijs, A.
van El, B.
Doornbos, R.P.
van Manen-Vernooij, B.C.T.
Bastiaans, J.H.M.W.
Penninks, A.H.
van Bilsen, J.H.M.
Cnubben, N.H.P.
de Groot, J.
Publication year
2011
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.
Subject
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
Nutrition
Anakinra
Biologics
Cytokines
IL-1 receptor antagonist
Immunotoxicity
Inflammation
Joint degradation markers
Pharmacokinetics
Rat adjuvant arthritis
Rheumatoid arthritis
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http://resolver.tudelft.nl/uuid:0062baa1-1c79-4ec1-93fa-c58349fefb94
DOI
https://doi.org/10.1016/j.yrtph.2011.01.014
TNO identifier
428335
ISSN
0273-2300
Source
Regulatory Toxicology and Pharmacology, 59 (3), 461-470
Document type
article