Mathematical Models in Pharmacodynamics

描述（由申请方提供）：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、药物分布至作用部位（生物相）、改变介质或受体水平的药物作用机制以及转换和转导过程。量化药理学反应的一个主要进展来自我们的认识，即不同的药效学作用可以使用一个家庭的四个基本（和扩展）间接反应模型的特点。这些（以及大多数）模型需要使用微分方程进行分析，而微分方程通常无法完全解析求解。该项目旨在表征和量化药物作用于周转过程的一般特性，这些周转过程对许多身体功能，结构或生物标志物非常重要。我们的具体目标包括进一步分析扩展的间接反应模型（有和没有前体隔室），用于单剂量研究无法预测的多剂量给药后的反应;继续开发基于多池寿命的间接反应模型，该模型模拟能够改变天然细胞周转或寿命的药物的造血和其他细胞分化级联反应;为药物作用改变靶表达细胞的周转、药物与内源性配体竞争以及药物结合机制本质上是变构或非竞争性的系统开发靶介导药物处置的高级药效学模型;以及机制的开发和评估-基于转运室的药效学模型，可以模拟细胞信号转导级联，并桥接分子生物学和宏观规模药效学反应，重点是抗癌药物。微积分和模拟的先进方法将被用来寻求这些模型的精确或近似的解决方案或行为，以确定如何控制响应的开始，程度，回报，持续时间，积分（通量）和响应的稳态，更容易从实验数据中恢复有意义的参数，并区分不同的模型来描述典型的数据集。这些努力将产生更好的见解和方法，用于理解和表征药物反应的时间过程，这些反应与生理学和药理学作用机制中表现出的主要药物和系统特异性特性有关。 公共卫生相关性：决定药物反应强度和时程的主要因素与身体如何处理药物、药理学作用机制以及生理结构和功能的转换有关。这些药物和系统性质是复杂的。该提案旨在利用数学和计算机建模来提高对药物如何引起其效应的理解。这样的努力使得能够整合大量信息以有效地探索新的药物靶标，并提供用于改善用于治疗各种疾病的现有药物的利用的方法。

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.