title: Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.
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 C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body 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.
authors.affiliation: TNO Quality of Life, Biosciences, The Netherlands. Anne-Marie.Zuurmond@tno.nl
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zuurmond
authors.forename: Angela
authors.initials: A
authors.lastname: Koudijs
authors.forename: Benno
authors.initials: B
authors.lastname: van El
authors.forename: Robert P
authors.initials: RP
authors.lastname: Doornbos
authors.forename: Babs C T
authors.initials: BC
authors.lastname: van Manen-Vernooij
authors.forename: Jacqueline H M W
authors.initials: JH
authors.lastname: Bastiaans
authors.forename: André H
authors.initials: AH
authors.lastname: Penninks
authors.forename: Jolanda H M
authors.initials: JH
authors.lastname: van Bilsen
authors.forename: Nicole H P
authors.initials: NH
authors.lastname: Cnubben
authors.forename: Jeroen
authors.initials: J
authors.lastname: Degroot
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D053590:Interleukin 1 Receptor Antagonist Protein / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1