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Modeling pharmacokinetics/pharmacodynamics of abatacept and disease progression in collagen-induced arthritic rats: a population approach

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Abstract

The PK/PD of abatacept, a selective T cell co-stimulation modulator, was examined in rats with collagen-induced arthritis (CIA) using a nonlinear mixed effect modeling approach. Male Lewis rats underwent collagen induction to produce rheumatoid arthritis. Two single-dose groups received either 10 mg/kg intravenous (IV) or 20 mg/kg subcutaneous (SC) abatacept, and one multiple-dose group received one 20 mg/kg SC abatacept dose and four additional 10 mg/kg SC doses. Effects on disease progression (DIS) were measured by paw swelling. Plasma concentrations of abatacept were assayed by enzyme-linked immunosorbent assay. The PK/PD data were sequentially fitted using NONMEM VI. Goodness-of-fit was assessed by objective functions and visual inspection of diagnostic plots. The PK of abatacept followed a two-compartment model with linear elimination. For SC doses, short-term zero-order absorption was assumed with F = 59.2 %. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (k in ) that was inhibited by abatacept. Variation in the PK data could be explained by inter-individual variability in clearance and central compartment volume (V 1 ), while the large variability of the PD data may be the result of paw edema production (k 0 in ) and loss rate constant (k out ). Abatacept has modest effects on paw swelling in CIA rats. The PK/PD profiles were well described by the proposed model and allowed evaluation of inter-individual variability on drug- and DIS-related parameters.

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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-La Roche Inc.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, 14214, USA

    Hoi-Kei Lon, Dongyang Liu, Debra C. DuBois, Richard R. Almon & 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. Hoi-Kei Lon
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  2. Dongyang Liu
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Correspondence to William J. Jusko.

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Lon, HK., Liu, D., DuBois, D.C. et al. Modeling pharmacokinetics/pharmacodynamics of abatacept and disease progression in collagen-induced arthritic rats: a population approach. J Pharmacokinet Pharmacodyn 40, 701–712 (2013). https://doi.org/10.1007/s10928-013-9341-1

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