Journal of Pharmacokinetics and Pharmacodynamics

, Volume 38, Issue 6, pp 769–786 | Cite as

Population pharmacokinetic–pharmacodynamic–disease progression model for effects of anakinra in Lewis rats with collagen-induced arthritis

  • Dongyang Liu
  • Hoi-Kei Lon
  • Debra C. DuBois
  • Richard R. Almon
  • William J. Jusko
Article

Abstract

A population pharmacokinetic–pharmacodynamic–disease progression (PK/PD/DIS) model was developed to characterize the effects of anakinra in collagen-induced arthritic (CIA) rats and explore the role of interleukin-1β (IL-1β) in rheumatoid arthritis. The CIA rats received either vehicle, or anakinra at 100 mg/kg for about 33 h, 100 mg/kg for about 188 h, or 10 mg/kg for about 188 h by subcutaneous infusion. Plasma concentrations of anakinra were assayed by enzyme-linked immunosorbent assay. Swelling of rat hind paws was measured. Population PK/PD/DIS parameters were computed for the various groups using non-linear mixed-effects modeling software (NONMEM® Version VI). The final model was assessed using visual predictive checks and nonparameter stratified bootstrapping. A two-compartment PK model with two sequential absorption processes and linear elimination was used to capture PK profiles of anakinra. A transduction-based feedback model incorporating logistic growth rate captured disease progression and indirect response model I captured drug effects. The PK and paw swelling versus time profiles in CIA rats were fitted well. Anakinra has modest effects (Imax = 0.28) on paw edema in CIA rats. The profiles are well-described by our PK/PD/DIS model which provides a basis for future mechanism-based assessment of anakinra dynamics in rheumatoid arthritis.

Keywords

Anakinra Pharmacokinetics Pharmacodynamics Rheumatoid arthritis Population model 

Notes

Acknowledgments

This work was supported by the UB Center for Protein Therapeutics, fellowship support for Dr. Liu from Hoffman-La Roche Inc., fellowship support for Ms. Lon from Amgen, Inc., and NIH Grant GM24211.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Dongyang Liu
    • 1
  • Hoi-Kei Lon
    • 1
  • Debra C. DuBois
    • 2
  • Richard R. Almon
    • 2
  • William J. Jusko
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at BuffaloBuffaloUSA
  2. 2.Department of Biological SciencesUniversity at BuffaloBuffaloUSA

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