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.
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