Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA.
J Pharmacokinet Pharmacodyn. 2011 Dec;38(6):769-86. doi: 10.1007/s10928-011-9219-z. Epub 2011 Oct 16.
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.
建立了群体药代动力学-药效动力学-疾病进展（PK/PD/DIS）模型，以描述在胶原诱导性关节炎（CIA）大鼠中阿那白滞素的作用，并探讨白介素-1β（IL-1β）在类风湿关节炎中的作用。CIA 大鼠接受载体、100mg/kg 阿那白滞素约 33 小时、100mg/kg 阿那白滞素约 188 小时或 10mg/kg 阿那白滞素约 188 小时皮下输注。通过酶联免疫吸附试验测定阿那白滞素的血浆浓度。测量大鼠后爪肿胀。使用非线性混合效应建模软件（NONMEM®Version VI）计算各组的群体 PK/PD/DIS 参数。使用视觉预测检查和非参数分层自举法评估最终模型。使用双室 PK 模型结合两个连续的吸收过程和线性消除来捕获阿那白滞素的 PK 曲线。纳入逻辑增长速率的基于转导的反馈模型用于捕获疾病进展，间接反应模型 I 用于捕获药物作用。CIA 大鼠的 PK 和爪肿胀与时间的曲线拟合良好。阿那白滞素对 CIA 大鼠的爪肿胀有适度的影响（I（max）=0.28）。我们的 PK/PD/DIS 模型很好地描述了这些曲线，为未来基于机制的类风湿关节炎中阿那白滞素动力学的评估提供了基础。
