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学的疾病进展模型提供建模和仿真平台，以了解氧诱导视网膜病变（OIR）的体内动态以及与非甾体抗炎药（NSAID）和全身咖啡因方案的复杂相互关系。我们基于人群的方法允许对患者、分子和环境特异性特征进行系统评估，这些特征可以解释疾病时间过程中的主体间变异性。将开发定量关系以捕获生物标志物表达的时间方面，用于测试治疗和辅助因素在多大程度上改变疾病进展的相互竞争的假设。这些信息还可用于优化这种联合用药方案的剂量和给药方案的选择。我们的核心教师在药物暴露-反应关系的发展方面拥有丰富的经验。药物和系统特性的建模和确定可以扩展到加强临床试验

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.