Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: Modeling interoccasion pharmacodynamic variability
Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: Modeling interoccasion pharmacodynamic variability
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DOI：
10.1007/s11095-006-9232-x
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发表时间：
2007-06-01
影响因子：
3.7
通讯作者：
Jusko, William J.
中科院分区：
文献类型：
--
作者：
Hong, Ying;Mager, Donald E.;Jusko, William J.
目的.开发一个群体药代动力学/药效学（PK/PD）模型，该模型表征主要全身性皮质类固醇对淋巴细胞运输和反应性的影响。在一项五向交叉、安慰剂对照研究中，向五名健康男性受试者给予单次（推测等效）剂量的静脉注射氢化可的松（HC）、地塞米松（DEX）、甲基强的松龙（MPL）和口服强的松龙（PNL）。测量包括血浆药物和皮质醇浓度，总淋巴细胞计数和全血淋巴细胞增殖（WBLP）。人口数据分析采用蒙特卡罗参数期望最大化算法。最后的间接，多成分，机制为基础的模型很好地捕捉了昼夜节律表现在皮质醇的生产和抑制，淋巴细胞运输，WBLP的时间配置文件。与PK参数相比，受试者之间产生50%最大免疫抑制的药物浓度（IC 50）的变异性较大（73-118%）。体外WBLP IC 50的对数转换后验贝叶斯估计值与体外测定值高度相关（r（2）= 0.928）。通过群体PK/PD模型充分描述了四种皮质类固醇的免疫抑制动力学，并结合了几个模型组分的时间间变异性。这项研究提供了改进的建模系统皮质类固醇的影响，并证明了更大的变异性的系统和动力学参数相比，药代动力学。
Purpose. To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness.Materials and Methods. Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five-way crossover, placebo-controlled study. Measurements included plasma drug and cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP). Population data analysis was performed using a Monte Carlo-Parametric Expectation Maximization algorithm.Results. The final indirect, multi-component, mechanism-based model well captured the circadian rhythm exhibited in cortisol production and suppression, lymphocyte trafficking, and WBLP temporal profiles. In contrast to PK parameters, variability of drug concentrations producing 50% maximal immunosuppression (IC50) were larger between subjects (73-118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC50 for ex vivo WBLP were highly correlated with those determined in vitro for the four drugs (r(2) = 0.928).Conclusions. The immunosuppressive dynamics of the four corticosteroids was well described by the population PK/PD model with the incorporation of inter-occasion variability for several model components. This study provides improvements in modeling systemic corticosteroid effects and demonstrates greater variability of system and dynamic parameters compared to pharmacokinetics.