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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-A)
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Suny Downstate Medical Center
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Nouri-Nigjeh, Eslam; Sukumaran, Siddharth; Tu, Chengjian et al. (2014) Highly multiplexed and reproducible ion-current-based strategy for large-scale quantitative proteomics and the application to protein expression dynamics induced by methylprednisolone in 60 rats. Anal Chem 86:8149-57
Tu, Chengjian; Mammen, Manoj Jacob; Li, Jun et al. (2014) Large-scale, ion-current-based proteomics investigation of bronchoalveolar lavage fluid in chronic obstructive pulmonary disease patients. J Proteome Res 13:627-39
An, Bo; Zhang, Ming; Qu, Jun (2014) Toward sensitive and accurate analysis of antibody biotherapeutics by liquid chromatography coupled with mass spectrometry. Drug Metab Dispos 42:1858-66
Tu, Chengjian; Li, Jun; Sheng, Quanhu et al. (2014) Systematic assessment of survey scan and MS2-based abundance strategies for label-free quantitative proteomics using high-resolution MS data. J Proteome Res 13:2069-79
Nouri-Nigjeh, Eslam; Zhang, Ming; Ji, Tao et al. (2014) Effects of calibration approaches on the accuracy for LC-MS targeted quantification of therapeutic protein. Anal Chem 86:3575-84
Qu, Jun; Young, Rebeccah; Page, Brian J et al. (2014) Reproducible ion-current-based approach for 24-plex comparison of the tissue proteomes of hibernating versus normal myocardium in swine models. J Proteome Res 13:2571-84
Gui, Shanying; Gathiaka, Symon; Li, Jun et al. (2014) A remodeled protein arginine methyltransferase 1 (PRMT1) generates symmetric dimethylarginine. J Biol Chem 289:9320-7
Shen, Xiaomeng; Young, Rebeccah; Canty, John M et al. (2014) Quantitative proteomics in cardiovascular research: global and targeted strategies. Proteomics Clin Appl 8:488-505
Chen, Ting; Mager, Donald E; Kagan, Leonid (2013) Interspecies modeling and prediction of human exenatide pharmacokinetics. Pharm Res 30:751-60
Beharry, Kay D; Cai, Charles L; Sharma, Poonam et al. (2013) Hydrogen peroxide accumulation in the choroid during intermittent hypoxia increases risk of severe oxygen-induced retinopathy in neonatal rats. Invest Ophthalmol Vis Sci 54:7644-57

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