Mathematical Models in Pharmacodynamics

描述（由申请人提供）：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率，药物在作用部位的分布（生物期），药物作用改变介质或受体水平的机制，以及转换和转导过程。我们认识到，不同的药效学效应可以用四种基本（和扩展的）间接反应模型来表征，这是量化药效学反应的一个重大进展。这些（和大多数）模型需要使用微分方程进行分析，而微分方程通常不能完全解析解决。该项目旨在描述和量化作用于代谢过程的药物的一般特性，这对许多身体功能、结构或生物标志物都很重要。我们的具体目标包括进一步分析扩展的间接反应模型（有或没有前体室），用于多剂量给药后单剂量研究无法预测的反应；继续发展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和其他细胞分化级联反应；在药物作用改变表达靶标细胞的周转、药物与内源性配体竞争、药物结合机制本质上是变构或非竞争的系统中，发展先进的靶标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估，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，重点是抗癌药物。将采用先进的微积分和模拟方法来寻求这些模型的精确或近似解或行为，以确定如何控制响应的开始，范围，返回，持续时间，响应的积分（通量）和稳态，从实验数据中更容易地恢复有意义的参数，并区分可用于描述典型数据集的各种模型。这些努力将产生更好的见解和方法，用于理解和描述药物反应的时间过程，这些反应与生理和药理作用机制所表现的主要药物和系统特异性特性有关。

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.