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

Abstract

Purpose 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 (kin) 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.

Biodistribution of Etanercept to Tissues and Sites of Inflammation in Arthritic Rats

“…This is a well-established animal model that mirrors human RA. We previously studied the plasma pharmacokinetics of etanercept using this animal model (Lon et al, 2011), and the present study extends our work by examining the tissue distribution kinetics of etanercept.…”

“…The induction of CIA in Lewis rats was performed following procedures described previously elsewhere (Earp et al, 2008;Lon et al, 2011). The required reagents were purchased from Chondrex (Redmond, WA).…”

“…A stepwise modeling approach was applied to characterize the plasma and tissue disposition of etanercept. First, plasma concentration profiles from the present study together with our previously published data (Lon et al, 2011) were fitted with a minimal physiologically based pharmacokinetics (mPBPK) model to describe the disposition of etanercept. The model includes plasma, lymph, and two lumped tissue compartments connected in an anatomic manner, as shown in Fig.…”

“…2 (Cao et al, 2013). The nonlinear absorption and mixed linear and MichaelisMenten elimination of etanercept in CIA rats were assumed based on previous studies (Lon et al, 2011). The linear clearance was assumed for healthy animals for simplicity.…”

“…The plasma pharmacokinetics of etanercept have been well studied in various species (Lon et al, 2011;Zhou et al, 2011). However, information on the distribution kinetics of etanercept to inflamed joint tissues is lacking.…”