title: Pharmacokinetic-pharmacodynamic disease progression model for effect of etanercept in Lewis rats with collagen-induced arthritis.
abstract: OBJECTIVE
  To develop a pharmacokinetic-pharmacodynamic disease progression (PK/PD/DIS) model to characterize the effect of etanercept in collagen-induced arthritis (CIA) rats on rheumatoid arthritis (RA) progression.
  
  
  METHODS
  The CIA rats received either 5 mg/kg intravenous (IV), 1 mg/kg IV, or 5 mg/kg subcutaneous (SC) etanercept at day 21 post-disease induction. Effect on disease progression was measured by paw swelling. Plasma concentrations of etanercept were assayed by enzyme-linked immunosorbent assay (ELISA). PK profiles were fitted first; parameter estimates were applied to fit paw edema data for PD and DIS-related parameter estimation using ADAPT 5 software.
  
  
  RESULTS
  The model contained a two-compartment PK model with Michaelis-Menten elimination. For SC administration, two additional mathematical functions for absorption were added. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (k(in)) assumed to be inhibited by etanercept.
  
  
  CONCLUSIONS
  Etanercept has modest effects on paw swelling in CIA rats. The PK and PD profiles were well described by the developed PK/PD/DIS model, which may be used for other anti-cytokine biologic agents for RA.
authors.affiliation: Department of Pharmaceutical Sciences School of Pharmacy & Pharmaceutical Sciences, University at Buffalo, Buffalo, New York 14260, USA.
authors.forename: Hoi-Kei
authors.initials: HK
authors.lastname: Lon
authors.forename: Dongyang
authors.initials: D
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Debra C
authors.initials: DC
authors.lastname: DuBois
authors.forename: Richard R
authors.initials: RR
authors.lastname: Almon
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept