期刊
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
卷 38, 期 6, 页码 769-786出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10928-011-9219-z
关键词
Anakinra; Pharmacokinetics; Pharmacodynamics; Rheumatoid arthritis; Population model
资金
- UB Center for Protein Therapeutics
- Hoffman-La Roche Inc.
- Amgen, Inc.
- NIH [GM24211]
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-1 beta (IL-1 beta) 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 (R) 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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