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Autoregulation in Brain and Dynamic Drug Delivery Modeling

This research summary by Dr. Andrej Mošat and Prof. A. Linninger explores the integration of autoregulation in brain functions with drug delivery systems and dynamic elastic vasculature. Utilizing first-principle models and empirical approaches, the report discusses Kinetic Inversion on Cyclosporine A using the Tanaka method on silicone rat hearts, focusing on vasculature network modeling and intrinsic hepatic clearance. Insights into multivariate pharmacokinetic models and optimal design for drug response are also highlighted, underscoring the need for global optimization methods in future research.

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Autoregulation in Brain and Dynamic Drug Delivery Modeling

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  1. Dr. Andrej Mošat` Prof. A. Linninger, Laboratory for Product and Process Design, M/C 063University of Illinois at Chicago 17 July 2010 Research Summary 07/2010

  2. Autoregulation in brain: • Equation generator for: • Drug delivery • Dynamic elastic vasculature

  3. First principle model

  4. Kinetic Inversion on Cyclosporine A case Tanaka’s Silicone Rat Heart: 4 ChambersSmooth muscle

  5. Kinetic Inversion on Cyclosporine A case2 min Bolus Injection

  6. Autoregulation on a model of vasculature • - Generated vasculature equation

  7. Semester Plan

  8. First principle model

  9. Empirical model vs. First principle model

  10. Approach to PBPK Modeling using Vasculature Network 1. 2. Intrinsic Hepatic Clearance Tanaka: CLi = F(Hct, t, organ type)Our proposal: CLi = F(Hct) => const. 4. Vasculature network combined with “tissue equations” Result:CCyA,i=F(t) 3. Kinetic organ models:F(CCyA(t, injection, CLliver, CLorgans ), params(Cplasma) ) 5. KIP for 1 parameter: CLi

  11. Literature Review Cierra found: Gueorguieva, I.; Aarons, L.; Ogungbenro, K.; Jorga, K.; Rodgers, T. & Rowland, M. Optimal Design for Multivariate Response Pharmacokinetic Models Journal of Pharmacokinetics and Pharmacodynamics, 2006, 33, 97-124 “We assume that measurements made at distinct times are independent, but measurements made of each concentration are correlated with a response variance--covariance matrix. “

  12. Outlook • Test rSQP for KIP of a “Rat50” model • Research Global optimization methods • Outline of a paper • REU preparation

  13. Experiment: Rats’ Blood and Tissue concentrations of CyA Blood Tissue concentration-to-time profiles of CyA in various organs of rats after 1.2- (circles), 6- (squares), and 30- (triangles) mg/kg doses. Each measurement in the unit of mg/ml or g represents an average value from three rats with S.D. (vertical bar). The solid line is log-linear interpolation between the measurements.

  14. ODE Solvers overview at our disposal

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