MATHEMATICAL MODELS IN PHARMACODYNAMICS

药效学中的数学模型

• 批准号: 6472622
• 负责人: WILLIAM J. JUSKO
• 金额: $ 4.39万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6472622
• 关键词: drug metabolism; mathematical model; pharmacokinetics

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.

描述（改编自研究者摘要）：主要因素 确定药理药物反应的是输入和处置 速率控制药代动力学、药物分布到部位 作用（生物相），药物作用改变介质或 受体水平，以及后者之后的转导过程。这 首席研究员制定了一家四口的间接应对措施 （IDR）模型来解释药物对反应介质的作用 而不是直接引起响应。因为这些 IDR 模型沿着 随着复杂性的增加，目前需要使用微分进行分析 通常无法完全积分的方程，主方程 研究人员建议使用先进的微积分和模拟方法 为此类模型寻求精确或近似的解决方案或行为 为了产生更好的洞察力和理解时间的方法 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 通过短期和长期输注给药时 IDR 的特性， 识别确定响应线性返回率的参数， 使用矩分析来表征实验数据，处理 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 而不是响应变量的可逆抑制。先进的 将采用微积分和模拟方法来寻求精确或 这些模型的近似解决方案或行为，以确定如何 发作、程度、返回、持续时间、AUC 和平均反应时间为 受控，更容易地从实验数据中恢复参数，以及 区分可用于描述各种类型的不同模型 的数据。这些努力应该会产生改进的见解和方法 了解与主要相关的药物反应的时间进程 行动机制。