MATHEMATICAL MODELS IN PHARMACODYNAMICS

描述(改编自《调查者摘要》)：主要因素 确定药物的药理反应是输入和处理 控制药物动力学的速率，药物分布到 作用(生物相)，药物作用于改变介质或 受体水平，以及跟随后者的转导过程。这个 首席调查员开发了一个由四人组成的间接反应家族 (IDR)模型来解释药物对反应中介物的作用 而不是直接引起反应。因为这些IDR模型 增加了复杂性，目前需要使用差异进行分析 经常不能完全积分的方程，主体 研究人员建议使用先进的方法进行微积分和模拟 寻求此类模型的精确或近似解或行为 以产生更好的洞察和理解时间的方法 与主要作用机制有关的药物反应过程。这 该项目致力于描述和量化药物作用的问题 直接机制和间接机制。具体目标包括：澄清 IDR的性质当药物通过短期和长期输注给药时， 识别确定响应的线性回报率的参数， 利用矩分析对实验数据进行表征，处理 可变基线行为，添加前驱体隔室 考虑到耐受性和反弹效应，并应用不可逆 而不是对响应变量的可逆抑制。进阶 将使用微积分和模拟的方法来寻求精确的或 这些模型的近似解或行为，以确定 起效时间、范围、恢复时间、持续时间、AUC和平均响应时间为 更容易地从实验数据中恢复参数，以及 在可用于描述各种类型的不同模型之间进行区分 数据。这些努力应该产生更好的洞察力和方法 了解药物反应与主要症状相关的时间进程 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.