Minimal physiologically-based pharmacokinetic (mPBPK) model for a monoclonal antibody against interleukin-6 in mice with collagen-induced arthritis.
Therapeutic monoclonal antibodies (mAb) targeting soluble inflammatory cytokines exert their pharmacological effects in rheumatoid arthritis through binding and neutralizing free cytokines in target tissue sites. Therefore suppression of free cytokines in such sites directly relates to the magnitude of therapeutic response. Although the interrelationships between mAb and cytokines have been examined in the systemic circulation, less is known about the interaction of mAb and cytokines in inflamed joints. In the present study, the interplay between the mAb, CNTO 345, and its target IL-6 in serum as well as ankle joint synovial fluid were characterized in collagen-induced arthritic mice. A minimal physiologically-based pharmacokinetic model with target-mediated drug disposition (TMDD) features in serum and ankle joint synovial fluid was developed for the assessment of the TMDD dynamics of CNTO 345 and IL-6. Our model indicates that TMDD kinetics in ankle joints differ greatly from that in serum. The differences can be attributed to the limited tissue distribution of CNTO 345 in ankle joint synovial fluid, the significant rise of the IL-6 baseline in ankle joint synovial fluid in comparison with serum, and the relative time-scales of elimination rates between CNTO 345, free IL-6 and CNTO 345-IL-6 complex in serum and ankle joint synovial fluid.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.|Biologics Clinical Pharmacology, Janssen R&D, 1400 McKean Road, Spring House, PA, 19447, USA.
Xi
X
Chen
Biologics Clinical Pharmacology, Janssen R&D, 1400 McKean Road, Spring House, PA, 19447, USA.
Xiling
X
Jiang
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
William J
WJ
Jusko
Quantitative Science, Janssen R&D, Spring House, PA, USA.|Biologics Clinical Pharmacology, Janssen R&D, 1400 McKean Road, Spring House, PA, 19447, USA.
Honghui
H
Zhou
Biologics Clinical Pharmacology, Janssen R&D, 1400 McKean Road, Spring House, PA, 19447, USA. wwang83@its.jnj.com.
Weirong
W
Wang
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology*; D008815:Mice, Inbred Strains; D008954:Models, Biological; D051381:Rats; D013582:Synovial Fluid / Q000737:chemistry / Q000276:immunology; D013640:Tarsal Joints / Q000187:drug effects* / Q000276:immunology; D014018:Tissue Distribution
D058846:Antibodies, Monoclonal, Murine-Derived; D015850:Interleukin-6; C577686:interleukin-6, mouse; D003094:Collagen
Minimal PBPK; Monoclonal antibody; Soluble cytokine; Target-mediated drug disposition in serum and synovial fluid; Tissue distribution