PHARMACOMETRICS (PKPD CORE) Subaward

药效学（PKPD CORE）子奖项

• 批准号: 8683209
• 负责人: DONALD E MAGER
• 金额: $ 2.66万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8683209
• 关键词: Adverse effects; Animals; Astrocytes; Bioinformatics; Biological Markers; Caffeine; Characteristics; Clinical; Clinical Data; Clinical Pharmacology; Clinical Protocols; Clinical Trials; Clinical Trials Design; Complex; DNA Damage; Data Analyses; Data Set; Deoxyguanosine; Development; Disease; Disease Progression; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Drug effect disorder; Endothelial Cells; Evaluation; Experimental Models; Faculty; Future; Genomics; Gestational Age; Human; Hyperoxia; Hypoxia; Ibuprofen; Insulin-Like Growth Factor I; Ketorolac; Link; Matrix Metalloproteinases; Measurement; Measures; Modeling; Molecular; Non-Steroidal Anti-Inflammatory Agents; Outcome; Oxidative Stress; Oxygen; Patients; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacodynamics; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Physiological; Physiology; Pre-Clinical Model; Process; Property; Proteomics; Protocols documentation; Rattus; Regimen; Research Personnel; Retina; Retinal; Retinal Diseases; Retinopathy of Prematurity; Risk Factors; Rodent; Safety; Schedule; Science; Signal Transduction; Signal Transduction Pathway; Structural Models; System; Systems Biology; Techniques; Testing; Therapeutic; Time; Toxicology; Treatment Protocols; Vascular Endothelial Growth Factors; angiogenesis; base; design; experience; improved; in vivo; inhibitor/antagonist; insight; isoprostaglandin F2alpha type-III; mathematical model; member; models and simulation; neonate; notch protein; pharmacodynamic model; population based; pre-clinical; prognostic; response; screening

The pharmacometrics core will provide modeling and simulation platforms for the construction of genomic and proteomic-based disease progression models to understand the in vivo dynamics of oxygen-induced retinopathy (OIR) and the complex interrelationships with combination nonsteroidal anti-inflammatory drug (NSAID) and systemic caffeine regimens. Our population-based approach allows for the systematic evaluation of patient, molecular, and environmental specific characteristics that explain inter-subject variability in the time-course of disease. Quantitative relationships will be developed to capture the temporal aspects of biomarker expression that will be used to test competing hypotheses of the extent to which treatment and co-factors modify disease progression. Such information may also be used to optimize the selection of dose and administration schedules of such combination drug regimens. Our core faculty members have extensive experience in the development of drug exposure-response relationships. Modeling and the determination of drug and system specific properties may be extended to enhance clinical trial design and data analysis, improve screening of compounds in development, and identify prognostic risk factors. For Protocol 1, nonlinear mixed effects pharmacokinetic/pharmacodynamic (PK/PD) models will be constructed and evaluated for understanding the exposure-response relationships of ocular ibuprofen or ketorolac with systemic caffeine in a rat experimental model of OIR. Model-based techniques will also be applied to facilitate the identification of the critical number of hyperoxic/hypoxic episodes resulting in abnormal angiogenesis in OIR. For Protocol 2, mechanism-based cellular PK/PD models will be developed to understand the influence of disease processes and drug effects in human retinal microvascular endothelial cells and astrocytes. Hyperoxia/hypoxia cycling and ibuprofen with or without caffeine concentrations will be linked to mathematical models of signal transduction (VEGF and Notch) and phenotypic outcomes. For Protocol 3, models developed from Protocols 1 and 2 will be scaled to inform and modify clinical protocols using translational modeling techniques developed within the core. Clinical data sets will be subsequently used to further refine clinical PK/PD models of retinopathy of prematurity (ROP) therapy using locally applied NSAIDS and systemic caffeine, better understand safety and efficacy, and provide a platform for the future individualization of ROP pharmacotherapy.

药理学核心将为构建基于基因组和蛋白质组学的疾病进展模型提供建模和模拟平台，以了解氧诱导视网膜病变（OIR）的体内动力学以及与非甾体抗炎药（NSAID）和全身性咖啡因方案的复杂相互关系。我们基于人群的方法允许系统评价患者、分子和环境特异性特征，这些特征解释了疾病时程中的受试者间变异性。将开发定量关系以捕获生物标志物表达的时间方面，其将用于测试治疗和辅助因素改变疾病进展的程度的竞争性假设。这样的信息还可以用于优化这样的组合药物方案的剂量和施用时间表的选择。我们的核心教师在药物开发方面有着丰富的经验。药物和系统特定性质的建模和确定可以扩展到增强临床试验 设计和数据分析，改进开发中化合物的筛选，并确定预后风险因素。对于方案1，将构建和评价非线性混合效应药代动力学/药效学（PK/PD）模型，以了解眼用布洛芬或酮咯酸与全身性咖啡因在OIR大鼠实验模型中的剂量-反应关系。还将应用基于模型的技术来促进识别导致OIR中异常血管生成的高氧/低氧发作的临界次数。对于方案2，将开发基于机制的细胞PK/PD模型，以了解疾病过程和药物作用对人视网膜微血管内皮细胞和星形胶质细胞的影响。高氧/缺氧循环和布洛芬（含或不含咖啡因浓度）将与信号转导（VEGF和Notch）和表型结果的数学模型相关联。对于方案3，将对方案1和2开发的模型进行缩放，以使用核心内开发的转化建模技术通知和修改临床方案。临床数据集随后将用于进一步完善使用局部应用的NSAIDS和全身性咖啡因的早产儿视网膜病变（ROP）治疗的临床PK/PD模型，更好地了解安全性和疗效，并为未来ROP药物治疗的个体化提供平台。