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

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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 (I max  = 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.

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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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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, 14260, USA

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

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

    Debra C. DuBois & Richard R. Almon

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  1. Dongyang Liu
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  2. Hoi-Kei Lon
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  3. Debra C. DuBois
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Correspondence to William J. Jusko.

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Liu, D., Lon, HK., DuBois, D.C. et al. Population pharmacokinetic–pharmacodynamic–disease progression model for effects of anakinra in Lewis rats with collagen-induced arthritis. J Pharmacokinet Pharmacodyn 38, 769–786 (2011). https://doi.org/10.1007/s10928-011-9219-z

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  • DOI: https://doi.org/10.1007/s10928-011-9219-z

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