Pharmacokinetic-Pharmacodynamic Disease Progression Model for Effect of Etanercept in Lewis Rats with Collagen-Induced Arthritis

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. 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. 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. 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.