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Semester report Semester Plan

01/05/2010 Dr. Andrej Mošať LPPD, UIC. Semester report Semester Plan. Goals. NSF Proposal Paper on Cyclosporin A PBPK Software AIChE 2010. Additional. Second paper led by Cierra ESCAPE 21 ISAT Report Solvers.V6 Supercomputer Proposal. Fall 2010 Semester Plan Publications.

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Semester report Semester Plan

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  1. 01/05/2010 Dr. Andrej Mošať LPPD, UIC Semester reportSemester Plan

  2. Goals • NSF Proposal • Paper on Cyclosporin A • PBPK Software • AIChE 2010 Additional • Second paper led by Cierra • ESCAPE 21 • ISAT Report • Solvers.V6 • Supercomputer Proposal

  3. Fall 2010 Semester PlanPublications • NSF Proposal for Drug Delivery – done • Paper “Mechanistic Modeling of Cyclosporine A Pharmacokinetics in Rats” - draft done • AIChE 2010 – 2 presentations and 1 poster, which won 2nd place in the CACE session • ESCAPE 21 – paper accepted • ISAT Technical Report • 2nd Paper with Cierra – results are now within reach, draft follows • Simulation of dynamic flow in deforming vessels, paper draft to be done

  4. Fall 2010 Semester PlanAlgorithms, coding • For the papers: needed to calculate 30 case studies on rat. Students calculated pig, monkey, human • Created a true PBPK Modeling Frameworkwhich is comparable in function with industrial effort of BAYER, Germany: e.g. MEDICI PK • Solvers V6, documented – done • Advised Seon's porting efforts • Simple Delphi Interface to NLP (Lancelot) with case studies - done

  5. Medici PK

  6. PBPK Software Select model … Administration mode … Duration of administration [min] Dosage [μg/ml] Body mass [kg] Hct (0.2 – 0.6) [w/w]

  7. PBPK Software overview ODE System: Equations from Delphi Report Class and Matlab script Delphi Network Tools: nwk, nwk2 Fitting and Optimization: Fortran , Lancelot Results: In some plotting package Drug data: Matlab Optimization and simulation results: GUI for students

  8. Spring 2011 Semester Plan • ESCAPE 21 – presentation • Paper with Cierra and Eric in progress • Paper with A. Lucia, Global Solver • Pharmacokinetic algorithmic paper, Quick prototype of basic ISAT technique algorithm • Investigate why TR method converges so slowly -> Sensitivity analysis?

  9. PBPK Framework • Inputs

  10. PBPK Framework • Preprocessing • Correct Data Mass (ug) Time (h)

  11. PBPK Framework • Calculate • Objective Function ? • Trust Region Method finds local optimum

  12. Mechanisms of species transport (Example on BBB) Brasnjevic, I. et al., Delivery of peptide and protein drugs over the blood–brain barrier

  13. PBPK Framework • Calculate • First order kinetics

  14. Results therapeutic 6 mg/kg bolus IV “Greedy Liver”

  15. Results – mass balance

  16. Results

  17. Results

  18. Is the solution acceptable? plasmaU 0.000000000000000E+000 liver 0.232808992116666 kidney 0.215965947452290 brain 0.322458656780916 bone 0.620987330418493 fat 0.362786743016428 gut 0.169726303638255 heart 0.128995063077219 lung 0.107479807749175 muscle 0.159658122723182 skin 0.328973223683983 spleen 5.940151968717812E-002 thymus 0.138495905081251 Blood 3.412716845396831E-002 Forgans(k)= 2.88186478387900 fmass= 0.258308592206578 F(k)= 3.14017337608558

  19. Results, various models • Therapeutic 6 mg/kg • “Greedy Liver” – optimal fit • “Tanaka model” – no renal clearance – slightly suboptimal fit • Normal liver mass transfer – suboptimal fit

  20. Results, optimized Subtherapeutic 1.2 mg/kg bolus IV Therapeutic 6 mg/kg bolus IV continuous 3, 6, 9, 12, 15, 30 mg/kg Supertherapeutic 30 mg/kg

  21. Optimal Therapy Selection Body mass … 9 Administration mode … Dosage [μg/ml] 6 Hct … 3 2 4 6 8 Duration of injection [hr]

  22. Rat network = Human network

  23. Mass balance "R:\matlab\from Eric\Cyclosporin A\20101030-FIG-CyA-Mass.jpg"

  24. Blood/Plasma "R:\matlab\from Eric\Cyclosporin A\20101030-FIG-CyA-Mass.jpg"

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