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 该计划首先旨在加深对药代动力学 (PK) 和机制的了解 皮质类固醇 (CS) 对与内分泌相关的基因组、蛋白质组和生理过程的影响， 急性和长期服用 CS 时，从局部到系统水平的代谢和药理学反应。 其次，提供潜在联合治疗的多种药物的作用和相互作用机制 第三，这些具体的研究结果将与相关研究相结合。 从文献中获取信息以开发改进的基于机制的 PK 和药效学 (PK/PD) 模型和方法涵盖基础、复杂和系统药理学层面并提供见解。 总体而言，我们的目标是开发机制药理学和疾病模型，揭示并相互关联 生物组织各个层次的“生物学和药理学规则”，并允许改进 体内激素和药物作用的定量和预测利用细胞培养物， 蛋白质组学和网络分析，重点是寻求多种药物的自然协同作用并不断发展 我们的 CS 研究实验范例非常广泛。 对接受特定条件或药物治疗的动物组进行仔细对照的研究（“巨鼠” 研究）将在一段时间内从雄性和雌性大鼠身上采集血液和主要器官，以反映其中任一情况。 内源性生物节律或单次药物剂量或延长药物剂量产生的变化的发生和恢复 我们检查了疾病和慢性药物暴露引起的体内平衡紊乱。 较长生物节律（发情周期、季节）内的短节律（昼夜节律），评估疾病中的性别差异 过程和类固醇作用，特别是在类风湿性关节炎中，并发展和应用生理相关 基本的 PK/PD 广泛应用于系统药理学方法和跨学科合作。 包括广泛的实验室实验、最先进的生物分析方法、“大数据”的生成 组学响应数据集、各种计算平台、有关不同生物的专业知识 过程，并提供想象力和洞察力来认识出现并构成基础的新原则 药物、激素和天然化合物如何在体内发挥作用和相互作用的复杂性。 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学 参与复杂药物作用机制的模型。 创新将提高对关键生物学、激素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。