PHARMACOMETRICS (PKPD CORE) Subaward

药物计量学核心将为构建基于基因组和蛋白质组的疾病进展模型提供建模和模拟平台，以了解氧气诱导视网膜病变(OIR)的体内动力学以及与非类固醇抗炎药(NSAID)和全身咖啡因联合疗法的复杂相互关系。我们的基于人群的方法允许系统地评估患者、分子和环境的特定特征，这些特征解释了疾病时间进程中的受试者之间的变异性。将开发定量关系以捕捉生物标记物表达的时间方面，这些生物标记物将用于测试治疗和辅助因素改变疾病进展程度的相互竞争的假设。这些信息也可用于优化这种联合用药方案的剂量和给药时间表的选择。我们的核心教员在药物暴露-反应关系的发展方面拥有丰富的经验。可以扩展药物和系统特定属性的建模和确定以增强临床试验 设计和数据分析，改进正在开发的化合物的筛选，并确定预后风险因素。对于方案1，将建立和评估非线性混合效应药代动力学/药效学(PK/PD)模型，以了解眼部布洛芬或酮洛酸与全身咖啡因在OIR大鼠实验模型中的暴露-反应关系。基于模型的技术也将被应用于帮助识别导致OIR异常血管生成的高氧/低氧发作的临界数量。对于议定书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效应对人视网膜微血管内皮细胞和星形胶质细胞的影响。有或没有咖啡因浓度的高氧/低氧循环和布洛芬将与信号转导(血管内皮生长因子和Notch)和表型结果的数学模型联系在一起。对于协议3，从协议1和协议2开发的模型将被缩放，以使用在核心内开发的转换建模技术来通知和修改临床协议。随后将利用临床数据集进一步完善临床PK/PD模型，使用局部应用的非类固醇类药物和全身咖啡因治疗早产儿视网膜病变(ROP)，更好地了解安全性和有效性，并为ROP药物治疗的未来个性化提供平台。

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.