Mathematical Models in Pharmacodynamics

描述(申请人提供)：决定药物反应的主要因素是控制药代动力学的输入和处置速率、药物在作用部位(生物相)的分布、药物在改变介体或受体水平时的作用机制以及周转和转导过程。在量化药理反应方面的一个重大进展来自于我们认识到，可以使用四个基本(和扩展的)间接反应模型来表征不同的药效作用。这些(和大多数)模型需要使用微分方程组进行分析，而这通常不能完全解析求解。该项目致力于表征和量化作用于周转过程的药物的一般性质，这些过程对许多身体功能、结构或生物标记物是重要的。我们的具体目标包括进一步分析单剂量研究无法预测的多剂量给药后反应的扩展间接反应模型(有和没有前体隔室)；继续开发基于多池寿命的间接反应模型，模拟能够改变自然细胞周转或寿命的药物的造血细胞和其他细胞分化级联；为药物作用改变靶向表达细胞的周转、药物与内源性配体竞争、药物结合的机制本质上是变构或非竞争性的系统开发先进的靶向介导药物处置的药效学模型；以及基于机制的转运室药效学模型的开发和评价，该模型可以模拟细胞信号转导级联，并将分子生物学和宏观药效学反应联系起来，重点放在抗癌药物上。先进的微积分和模拟方法将被用来寻求这些模型的精确或近似的解或行为，以确定如何控制响应的起始、范围、返回、持续时间、响应的积分(通量)和响应的稳定状态，更容易地从实验数据中恢复有意义的参数，并区分可用于描述典型数据集的不同模型。这些努力将产生更好的洞察力和方法，以了解和表征药物反应的时间进程，因为这些时间进程与主要的药物和系统特有的特性有关，体现在生理和药理作用机制上。 公共卫生相关性：决定药物反应强度和时间进程的主要因素与人体如何处理药物、药理作用机制以及生理结构和功能的周转有关。这些药物和系统的性质是复杂的。这项提议寻求利用数学和计算机建模来提高对药物如何产生效果的理解。这些努力能够整合大量信息，有效地探索新的药物靶点，并为提高现有药物治疗各种疾病的利用率提供方法。

DESCRIPTION (provided by applicant): The major factors determining drug responses are the input and disposition rates controlling pharmacokinetics, drug distribution to the site of action (biophase), the mechanism of drug action in altering mediator or receptor levels, and turnover and transduction processes. A major advance in quantifying pharmacologic responses came from our recognition that diverse pharmacodynamic effects can be characterized using a family of four basic (and extended) indirect response models. These (and most) models require analysis using differential equations which usually cannot be fully solved analytically. This project seeks to characterize and quantify the general properties of drugs acting on turnover processes which are important for numerous body functions, structures, or biomarkers. Our specific aims include further analysis of extended indirect response models (with and without precursor compartments) for responses following multiple dose administration that are not predictable from single- dose studies; continued development of multiple-pool lifespan-based indirect response models that mimic hematopoietic and other cellular differentiation cascades for drugs capable of altering the turnover or life-span of natural cells; development of advanced pharmacodynamic models of target-mediated drug disposition for systems where drug action alters the turnover of target-expressing cells, drug competes with endogenous ligands, and the mechanism of drug binding is allosteric or noncompetitive in nature; and the development and evaluation of mechanism-based transit compartment pharmacodynamic models that can emulate cellular signal transduction cascades and bridge molecular biology and macro- scale pharmacodynamic responses with a focus on anticancer drugs. Advanced methods of calculus and simulations will be employed to seek exact or approximate solutions or behaviors of these models to identify how the onset, extent, return, duration, integrals of response (flux), and steady-states of response are controlled, to recover meaningful parameters more easily from experimental data, and to discriminate among diverse models available to describe typical data sets. These efforts will yield improved insights and methods for understanding and characterizing the time-course of drug responses as related to major drug- and system-specific properties manifesting from mechanisms of physiology and pharmacologic action. PUBLIC HEALTH RELEVANCE: The major factors determining the intensity and time-course of drug responses are related to how the body processes the drug, pharmacologic mechanisms of action, and turnover of physiologic structures and functions. These drug and system properties are complex. This proposal seeks to utilize mathematical and computer modeling to improve the understanding of how drugs elicit their effects. Such efforts enable the integration of large amounts of information to efficiently explore new drug targets and provide methods for improving utilization of current drugs for treating various diseases.