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

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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 (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.

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ACKNOWLEDGMENTS

This work was supported by funding from the UB Center for Protein Therapeutics, NIH Grant GM 24211, a fellowship for Ms. Lon from Amgen, Inc., and fellowship support for Dr. Liu from Hoffman-LaRoche Inc.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences School of Pharmacy & Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, 14260, USA

    Hoi-Kei Lon, Dongyang Liu, Qi Zhang & William J. Jusko

  2. Department of Biological Sciences, University at Buffalo, Buffalo, New York, 14260, USA

    Debra C. DuBois & Richard R. Almon

Authors
  1. Hoi-Kei Lon
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  2. Dongyang Liu
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  3. Qi Zhang
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  4. Debra C. DuBois
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  5. Richard R. Almon
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  6. William J. Jusko
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Correspondence to William J. Jusko.

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Lon, HK., Liu, D., Zhang, Q. et al. Pharmacokinetic-Pharmacodynamic Disease Progression Model for Effect of Etanercept in Lewis Rats with Collagen-Induced Arthritis. Pharm Res 28, 1622–1630 (2011). https://doi.org/10.1007/s11095-011-0396-7

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  • DOI: https://doi.org/10.1007/s11095-011-0396-7

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