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Mechanistic Pharmacokinetics and Pharmacodynamics

机制药代动力学和药效学

基本信息

批准号：
10614070
负责人：
WILLIAM J. JUSKO
金额：
$ 59.78万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614070
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 Natural Compound 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 biological systems circadian computational platform drug action experimental study improved in vivo innovation insight interdisciplinary collaboration male mathematical model pancreatic cancer cells pharmacodynamic model pharmacokinetics and pharmacodynamics pharmacologic physiologic model programs response synergism

项目摘要

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.

摘要该计划旨在首先提供更多的了解药代动力学（PK）和机制，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，代谢和药理学反应，从局部到系统水平的CS急性和慢性给药。其次，提供潜在的联合治疗的多种药物的作用机制和相互作用，将检查胰腺癌。第三，这些具体的研究成果将与相关的文献中的信息，以开发基于机制的PK和药效学（PK/PD）改进模型和方法跨越并提供基本，复杂和系统药理学水平的见解。总的来说，我们的目标是发展机制药理学和疾病模型，揭示和相互关联生物学和药理学规则“在生物组织的各个层次，并允许改进体内激素和药物作用的定量和预测。癌症药物研究利用细胞培养，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，定量药物相互作用的新方法。我们的CS研究的实验范式一直很大在动物组中进行的仔细对照研究，这些动物经受规定的条件或药物治疗（“巨鼠”），研究）。将在反映以下情况的时间范围内从雄性和雌性大鼠中采集血液和主要器官：内源性生物节律或单次给药或长期给药引起的变化的发生和恢复疾病和慢性药物暴露引起的体内平衡紊乱。我们研究了在较长的生物节律（发情周期，季节）内的短节律（昼夜节律），评估疾病的性别差异过程和类固醇作用，特别是在类风湿性关节炎，并发展和应用生理相关从基本的PK/PD到广泛的系统药理学方法。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、“大数据”的生成组学响应数据集，各种计算平台，关于各种生物学的专家知识，过程，并提供想象力和洞察力，以认识新的原则，出现和基础，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基础PK/PD和系统建模，但重点是增强生理参与药物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，并将继续提供广泛的应用在定量药理学。