Mathematical Models in Pharmacodynamics

药效学数学模型

• 批准号: 7094873
• 负责人: WILLIAM J. JUSKO
• 金额: $ 26.1万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094873
• 关键词: active sites; biomarker; cell cycle; drug administration rate /duration; drug interactions; drug metabolism; drug receptors; inhibitor /antagonist; mathematical model; pharmacokinetics

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 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 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 continued development of extended indirect models for responses generated from a precursor pool as relevant for most hormones and endogenous substances, explore multi-pool lifespan based indirect response models accounting for variability of lifespans of most cells derived from the hematopoietic system, develop advanced models for drugs with target-mediated disposition accounting for several possible control factors and turnover of reactive sites as relevant for a growing array of biotechnology products, and extend indirect response models to handle several types of drug-drug interactions which describe natural synergy and apply to many joint effects of drugs such as immunosuppressants and chemotherapeutic agents. 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, integrals of response, and steady-state of responses are controlled, to recover parameters more easily from experimental data, and to discriminate among diverse models available to describe typical data. This research addresses the considerable need in drug development for better strategies for utilizing biomarkers and for quantitating and predicting drug effects. These efforts will yield improved insights and methods for understanding and characterizing the time-course of drug responses as related to major mechanisms of physiology and pharmacologic action.

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速率、药物分布到作用位点（生物相）、改变介质或受体水平的药物作用机制以及周转和转导过程。定量药理反应的重大进展来自于我们认识到可以使用四个基本（和扩展）间接反应模型来表征不同的药效效应。这些（以及大多数）模型需要使用微分方程进行分析，而微分方程通常无法完全解析求解。该项目旨在表征和量化作用于周转过程的药物的一般特性，这对于许多身体功能、结构或生物标志物很重要。我们的具体目标包括继续开发扩展的间接模型，用于与大多数激素和内源性物质相关的前体池产生的反应，探索基于多池寿命的间接反应模型，解释来自造血系统的大多数细胞寿命的变异性，开发具有靶标介导处置的先进药物模型考虑了与越来越多的生物技术产品相关的几种可能的控制因素和反应位点的周转，并扩展了间接响应模型以处理几种类型的药物-药物相互作用，这些模型描述了自然协同作用并应用到免疫抑制剂和化疗药物等多种药物的联合作用。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决方案或行为，以确定如何控制响应的开始、程度、返回、持续时间、响应积分和响应稳态，以更多地恢复参数轻松地从实验数据中提取数据，并区分可用于描述典型数据的各种模型。这项研究满足了药物开发中对利用生物标志物以及定量和预测药物作用的更好策略的巨大需求。这些努力将产生更好的见解和方法，用于理解和表征与生理学和药理作用的主要机制相关的药物反应的时间过程。