MATHEMATICAL MODELS IN PHARMACODYNAMICS

药效学中的数学模型

• 批准号: 6624513
• 负责人: WILLIAM J. JUSKO
• 金额: $ 21.95万
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624513
• 关键词: drug administration rate /duration; drug metabolism; drug receptors; inhibitor /antagonist; mathematical model; pharmacokinetics; receptor binding; stimulant /agonist

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 level, and transduction processes. May improvements in quantitating 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 integrated. This project seeks to characterize and quantify the properties of drugs acting by diverse mechanisms. Specific aims include development of a compendium with comparison of the array of relevant mechanism-based PK/PD models, further development of indirect response models with a precursor compartment including the occurrence of feedback alterations; evolution of extended indirect lifespan models for application to natural cell responses including effects such as bone marrow stimulation and/or cytotoxicity; and the detailed characterization of non-linear and time- dependent transduction models which may be applied to numerous membrane receptor (e.g., G-protein) mediated responses. Advanced methods of calculus and stimulations will be employed to seek exact or approximate solutions or behaviors for these models to identify how the onset, extent, return, duration, AUC, and steady-stage of responses are controlled, to recovery parameters more easily from experimental data, and to discriminate among diverse models available to describe typical data, and to determine how to optimize drug dosing regimens. These efforts will yield insights, methods, and resources for understanding and quantitating the time course of drug responses as related to major mechanisms of action.

确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，药物分布到作用部位（生物相），改变介质或受体水平的药物作用机制以及转导过程。我们认识到，可以使用四种基本（和扩展）间接反应模型的家族来表征不同的药效动力学效应，这可能会改善定量药理学反应。这些（和大多数）模型需要使用通常无法完全集成的微分方程进行分析。该项目旨在表征和量化通过各种机制作用的药物的特性。具体目的包括开发汇编，并比较基于相关机制的PK/PD模型，进一步开发具有前体隔室的间接响应模型，包括发生反馈改变的发生；扩展间接寿命模型的演变，用于应用自然细胞反应，包括诸如骨髓刺激和/或细胞毒性之类的作用；以及可以应用于众多膜受体（例如G蛋白）介导的反应的非线性和时间依赖转导模型的详细表征。将采用微积分和刺激的先进方法来寻求这些模型的精确或近似解决方案或行为，以确定如何控制发作，程度，返回，持续时间，持续时间，AUC和稳态响应阶段，从实验数据中更容易地从实验数据中更容易地恢复参数，并在不同的模型中区分可用的模型来描述典型的数据，以确定典型的数据，并确定如何优化药物的药物。这些努力将产生与主要作用机制有关的毒品反应时间过程的见解，方法和资源。