Krzyzanski W, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260, USA.
J Pharmacokinet Biopharm. 1997 Feb;25(1):107-23. doi: 10.1023/a:1025723927981.
Four basic models for characterizing indirect pharmacodynamic responses were proposed previously and applied using differential equations. These models consider inhibition or stimulation by drug of the production or loss of mediators or response variables. This report develops partially integrated solutions for these models which allow more detailed examination of the roles of model parameters and pharmacokinetic functions in affecting the time course of drug effects. Because of the nonlinear Hill function, the solutions are represented by means of definite integrals containing kinetic and dynamic functions. These solutions allow a qualitative examination, using calculus, of how response is controlled by Dose, IC50 or SC50, Imax or Smax, and kout for drugs exhibiting monotonic or biphasic disposition. Characteristics of the response curves that were identified include shape, maximum or minimum, and changes with the above parameters and time. These relationships, together with simulation studies, provide a fundamental basis for understanding the temporal aspects of the basic indirect response models.
先前提出了四种用于表征间接药效学反应的基本模型，并使用微分方程进行了应用。这些模型考虑药物对介质或反应变量产生或损失的抑制或刺激作用。本报告为这些模型开发了部分积分解决方案，从而能够更详细地研究模型参数和药代动力学函数在影响药物效应时间过程中的作用。由于非线性希尔函数，这些解决方案通过包含动力学和动态函数的定积分来表示。这些解决方案允许使用微积分对表现出单调或双相处置的药物，通过剂量、IC50或SC50、Imax或Smax以及kout来定性研究反应是如何被控制的。所识别的反应曲线特征包括形状、最大值或最小值，以及随上述参数和时间的变化。这些关系与模拟研究一起，为理解基本间接反应模型的时间方面提供了基础。
