MATHEMATICAL MODELS IN PHARMACODYNAMICS

描述（改编自研究者摘要）：主要因素 确定药理学药物反应是输入和处置 控制药代动力学的速率，药物分布到 作用（生物相），改变介质或 受体水平，以及随后的转导过程。的 主要研究者开发了一系列四种间接反应 (IDR)解释药物对反应介质作用的模型 而不是直接引起反应。因为这些IDR模型沿着 随着复杂性的增加，目前需要使用差分 方程往往不能完全集成，主要的 研究人员建议使用先进的方法进行微积分和模拟 为这些模型寻求精确或近似的解或行为， 为了产生更好的见解和方法来理解时间， 与主要作用机制相关的药物反应过程。这 该项目旨在描述和量化毒品问题， 直接和间接机制。具体目标包括：阐明 当通过短期和长期输注给予药物时IDR的性质， 识别确定响应的线性返回率的参数， 利用矩分析来表征实验数据， 可变的基线行为，添加前体隔室， 考虑耐受性和反弹效应，并应用不可逆转 而不是对反应变量的可逆抑制。先进 微积分和模拟的方法将被用来寻求精确的或 这些模型的近似解或行为，以确定 起效时间、程度、恢复时间、持续时间、AUC和平均缓解时间 控制，更容易从实验数据中恢复参数， 区分可用于描述各种类型的不同模型， 的数据.这些努力应产生更好的见解和方法， 了解药物反应的时间过程与主要 行动机制。

DESCRIPTION (Adapted from Investigator's Abstract): The major factors determining pharmacologic 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 transduction processes which follow the latter. The Principal Investigator has developed a family of four indirect response (IDR) models to account for drug action on the mediators of the response rather than directly causing the response. Because these IDR models along with added complexities currently require analysis using differential equations which often cannot be fully integrated, the Principal Investigator proposes to use advanced methods for calculus and simulation to seek exact or approximate solutions or behaviors for such models in order to yield improved insights and methods for understanding the time course of drug response as related to major mechanisms of action. This project seeks to characterize and quantify the problem of drugs acting by direct and indirect mechanisms. Specific aims include: elucidating properties of IDR when drug is given by short and long-term infusions, identifying parameters determining the linear return rates of responses, using moment analysis to characterize experimental data, dealing with variable baseline behaviors, addition of a precursor compartment to account for tolerance and rebound effects, and applying irreversible rather than reversible inhibition of the response variable. Advanced methods of calculus and simulations will be employed to seek exact or approximate solutions or behaviors for these models, to identify how the onset, extent, return, duration, AUC, and mean times of responses are controlled, to recover parameters more easily from experimental data, and to discriminate among diverse models available to describe various, types of data. These efforts should yield improved insights and methods for understanding the time course of drug responses as related to major mechanisms of action.