Mechanistic Pharmacokinetics and Pharmacodynamics

机制药代动力学和药效学

• 批准号: 9922338
• 负责人: WILLIAM J. JUSKO
• 金额: $ 59.85万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922338
• 关键词: Acute; Adrenal Cortex Hormones; Advanced Development; Animals; Antineoplastic Agents; Big Data; Biological; Biological Models; Biological Process; Biology; Bioperiodicity; Blood; Cell Culture Techniques; Chronic; Clinical; Complement; Complex; Controlled Study; Data; Data Set; Development; Disease; Disease model; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Endocrine; Estrous Cycle; Female; Generations; Genomics; Goals; Harvest; Homeostasis; Hormones; Imagination; Joints; Knowledge; Laboratories; Literature; Malignant neoplasm of pancreas; Metabolic; Methodology; Methods; Organ; Pathway Analysis; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Physiological Processes; Process; Proteomics; Rattus; Recovery; Rheumatoid Arthritis; Seasons; Sex Differences; Signal Pathway; Steroids; Study models; System; Therapeutic Agents; Tissues; Work; base; biological systems; circadian; computational platform; drug action; experimental study; improved; in vivo; innovation; insight; interdisciplinary collaboration; male; mathematical model; pancreatic cancer cells; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; physiologic model; programs; response; synergism

Abstract This program seeks firstly to provide increased understanding of pharmacokinetics (PK) and mechanisms of corticosteroid (CS) effects on genomic, proteomic, and physiologic processes associated with endocrine, metabolic, and pharmacologic responses from local to systems levels for CS dosed acutely and chronically. Secondly, the mechanisms of action and interaction of multiple agents offering potential joint therapy of pancreatic cancer will be examined. Thirdly, these specific study results will be integrated with relevant information from the literature to develop improved mechanism-based PK and pharmacodynamic (PK/PD) models and methods spanning and offering insights at basic, complex, and systems pharmacologic levels. Overall, our goals are development of mechanistic pharmacologic and disease models that reveal and interrelate the `rules of biology and pharmacology' at various levels of biological organization and allow improved quantitation and prediction of in vivo hormone and drug effects. The cancer drug studies utilize cell cultures, proteomics, and network analyses with an emphasis on seeking natural synergy of multiple agents and evolving new methods for quantitating drug interactions. Our experimental paradigm for CS studies has been large carefully controlled studies in groups of animals subjected to defined conditions or drug treatments (“giant rat” studies). Blood and major organs will be harvested from male and female rats over timeframes reflecting either endogenous biorhythms or the onset and recovery of changes produced by single drug doses or prolonged disturbances of homeostasis produced by disease and chronic drug exposures. We examine involvement of short rhythms (circadian) within longer biorhythms (estrous cycle, seasons), assess sex differences in disease processes and steroid actions particularly in rheumatoid arthritis, and evolve and apply physiologically relevant basic PK/PD to extensive systems pharmacologic approaches. Our methods and interdisciplinary collaborations include extensive laboratory-based experiments, state-of-the-art bioanalysis methods, generation of “big data” sets of –omics response data, various computational platforms, expert knowledge about diverse biological processes, and offer the imagination and insights to recognize new principles that emerge and underlie the complexities of how drugs, hormones, and natural compounds work and interact in the body. These efforts encompass and enrich both basic PK/PD and systems modeling, but with emphasis on enhanced physiological models that attend complex mechanisms of drug action. These holistic studies and mathematical modeling innovations will provide improved multi-scale understanding of critical biological, hormone, and pharmacologic functions and will continue to offer wide applications in quantitative pharmacology.

抽象的 该计划首先旨在提供对药代动力学（PK）和机制的更多了解 皮质类固醇（CS）对与内分泌相关的基因组，蛋白质组学和生理过程的影响 急性和慢性剂量的CS的代谢和药学反应。 其次，多种试剂的作用机理和提供潜在关节治疗的相互作用的机理 将检查胰腺癌。第三，这些具体的研究结果将与相关的 来自文献的信息开发了改进的基于机制的PK和药效学（PK/PD） 模型和方法涵盖并提供基本，复杂和系统药物级别的见解。 总体而言，我们的目标是揭示和相互关联的机械药物和疾病模型的开发 各级生物组织的“生物学和药理学规则”，并允许改进 体内赛酮和药物作用的定量和预测。癌症药物研究利用细胞培养物， 蛋白质组学和网络分析，重点是寻求多种代理的自然协同作用并发展 定量药物相互作用的新方法。我们用于CS研究的实验范式很大 在经受固定疾病或药物治疗的动物组中仔细控制的研究（“巨型大鼠”） 研究）。鲜血和主要器官将从雄性和雌性大鼠随时随地收获，以反映出这 内源性生物节律或单一药物剂量产生的变化或延长的变化 疾病和慢性药物暴露引起的体内平衡的障碍。我们研究了 在更长的生物节律（发情周期，季节）内的短节奏（昼夜节律），疾病评估性别差异 过程和类固醇的作用，尤其是在类风湿关节炎中，并进化和应用物理相关 基本的PK/PD到广泛的系统药物方法。我们的方法和跨学科合作 包括广泛的基于实验室的实验，最先进的生物分析方法，生成“大数据” –omics响应数据集，各种计算平台，有关潜水员生物学的专家知识 流程，并提供想象力和见解，以认识到出现和构成的新原则 药物，激素和天然化合物如何在体内起作用和相互作用的复杂性。这些努力 涵盖并丰富了基本的PK/PD和系统建模，但重点是增强的生理 参加毒品作用的复杂机制的模型。这些整体研究和数学建模 创新将提供对关键生物学，本人和药理学的多尺度理解 功能，并将继续在定量药理学中提供广泛的应用。