Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York, 14260, USA.
Pharm Res. 2010 May;27(5):920-32. doi: 10.1007/s11095-010-0098-6. Epub 2010 Mar 16.
To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD).
PK and PD profiles of human IFN-beta1a, IFN-beta1b, and IFN-alpha2a in humans, monkeys, rats, and mice from nine studies were extracted from the literature by digitization. Concentration-time profiles from different species were fitted simultaneously using various allometric relationships to scale model-specific parameters.
PK/PD profiles of IFN-beta1a in humans and monkeys were successfully characterized by utilizing the same rate constant parameters and scaling the volume of the central compartment to body weight using an allometric exponent of 1. Concentration and effect profiles of other IFNs were also well described by changing only the affinity of the drug to its receptor. PK profiles in rodents were simulated using an allometric exponent of -0.25 for the first-order elimination rate constant, and no receptor-binding was included given the lack of cross-reactivity.
An integrated TMDD PK/PD model was successfully combined with classic allometric scaling techniques and showed good predictive performance. Several parameters obtained from one IFN can be effectively shared to predict the kinetic behavior of other IFN subtypes.
开发一种综合的基于机制的建模方法，用于对具有靶介导药物处置（TMDD）的 I 型干扰素（IFN）的药代动力学（PK）和药效学（PD）特性进行种间缩放。
通过数字化从文献中提取了来自九项研究的人类 IFN-β1a、IFN-β1b 和 IFN-α2a 在人类、猴子、大鼠和小鼠中的 PK 和 PD 谱。使用各种比例关系同时拟合不同物种的浓度-时间曲线，以对模型特异性参数进行缩放。
通过使用相同的速率常数参数，并使用 1 的比例指数将中央室体积缩放为体重，成功地描述了 IFN-β1a 在人类和猴子中的 PK/PD 谱。通过仅改变药物与其受体的亲和力，也可以很好地描述其他 IFN 的浓度和效应谱。使用 -0.25 的比例指数对一级消除速率常数进行啮齿动物 PK 曲线模拟，由于缺乏交叉反应性，因此不包括受体结合。
成功地将综合的 TMDD PK/PD 模型与经典的比例缩放技术相结合，并显示出良好的预测性能。从一种 IFN 获得的几个参数可以有效地共享，以预测其他 IFN 亚型的动力学行为。
