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1. 39 T3 DUAL MONITOR SUPPORT ila 39 8 MODELSSTORAGE z 22289500 ccc sds 29090208 ali 87192200213 602500 901902852 41 S1 PEPATI A II 41 5 2 FORMATSELECTONa 41 d UMORE 42 9 FITTING MODELS TO OBSERVATIONS eee eee eese ee eee eese sese sesso sees eee 43 91 ADDING OBSERVATIONS S RM EM ME EE MI EIE C MM EIDEM EIE 43 92 SELECTING PARAMETERS iena 43 ADET TNO 43 PEOR OET e E EE ATE E O EA E AE E E E EAE 43 LEE Sr uu B EC NS rain nile 44 IO MONTIECARIOSIMULATODB ori Pens IRI ini 44 e IERUE 1e 44 11 PROGRAMMING ESM ia E 45 VA CROSS en E 45 46 12 IL lia 47 LI POSA EREORMESSACE S2. Macro and object code is actually beyond the scope of this manual But you can already learn a lot from converting model diagrams into macros and by viewing the code of existing objects 46 MEDIWARE Appendices 12 APPENDICES 12 1 Edsim Error Messages ModLib LinkSourceException Object A cannot be the source of target object B Source must be of type T LinkTargetException Object A cannot be the target of source object B Target must be of type T LinkInCountException Object A cannot have more than N source s LinkOutCountException Object A cannot have more than N target s UnresolvedSymbolException Symbol S in object A has not been resolved by any of the connected objects Objects may be incompatible or links missing InstanceNotAllowedException Object A is of type T You are not allowed to create instances of this type because it is marked with the Nolnstance attribute OneInstanceAllowedException Only one object of type T is allowed because it is marked with the Onelnstance attribute CircularReferenceException Parameters P and Q reference each other for sharing circular reference HiddenFieldException Hidden field F detected in class C This is not allowed Rethink inheritance strategy ModWrk UnknownObjectException Reference to unknown object A UnknownSymbolException Reference to unknown symbol S NumLib IterationException Too many steps in procedure P ModSim UserAbortException The simulation was aborted by the use
3. Now connect injection 101 source with the compartment C01 target Next connect compartment C01 source with the elimination O01 target C01 TCompartment O01 TElimination NM 101 TInjection Next click on the mini chart button 22 followed by the run button on the toolbar 001 TElimination 101 Tinjection 439 MEDIWARE Building Models One of the great features of Edsim is that all objects are equipped with smart default values so that when you are done building a model you can directly simulate it Now double click the elimination object 001 Select the parameters tab Par and increase the elimination rate constant from 0 1 to 0 5 1 h Run a simulation again NN NN NN NN 7 x Compartment 001 TElimination Se P QD 101 TInjection Note how the concentration profile has changed Now click on the Results tab at the top followed by clicking on the Symbols sub tab at the bottom of the application window Closely look at the parameters lists All non default parameters are marked with a yellow color This will help you to identify those parameters you forgot to enter yourself Please note that all data in the Results tab is only updated after a simulation Parameters COl V 11 001 22 051 Now double click the elimination object 001 again Select the options tab Opt
4. MEDIWARE Quick Start 3 4 Modify a Model Add another event dosing sequence of 5 times 150 mg every 12 hours starting at 100 h Dose Tnul Tdur Tint Ndos Now start another simulation by clicking the Run button TPeripheral en C04 TPeripheral C01 C03 Compartment TPeripheral 101 001 Tinjection TElimination Click the right mouse button to bring up a magnifying glass 14 MEDIWARE Quick Start 3 5 Decorate a Model Select the TElimination object 001 by clicking on it Now click on the Select Image button In the File Open dialog select the kidney wmf image file in the Anatomy folder The image will be displayed in the 001 object Repeat this for the C04 object Anatomy Brain wmf and the 101 object Admin Injection wmf You have now decorated the model C04 C01 C03 TPeripheral Compartment TPeripheral 101 001 TInjection TElimination 15 MEDIWARE Edsim Desktop 4 EDSIM DESKTOP 4 1 Overview Below is an image of the Edsim desktop All important elements are clearly identified File Model Macro Object o 01 O Type TCompartment OBJECT Name Type TCompartment idi Molecular Weight Sync Object Interactant L Color 2013 Mediware a s All rights reserved Platform Microsoft Windows NT 6 1 7601 Service Pack 1 AMD64 Ma
5. Un Un 38 MEDIWARE Results Viewer 7 2 7 3 You can do all things in the results viewer that you can also do in regular spreadsheets You can enter formulas into cells but you can also create embedded charts Workbook Designer Mode You can create a 2nd copy of the results viewer outside the Edsim application window by right clicking the spreadsheet Then select Workbook Designer from the context menu al C Mediware Edsim Models EDX Groningen20 File Model Object Help O IJ s Type Model Macro Results A B C D E F G H 1 K L M 1 SIMULATION OUTPUT LAI 2 3 Index Type Sys Tsim Tol C Ins C Glu C 4 h mg L mU L mg dl 5 0 Norm 0 0 5 90 6 1 Norm 0 048 0 5 90 7 2 Norm 0 096 0 5 90 8 3 Norm 0 144 0 5 90 n ud SpreadsheetGear Workbook Designer C Mediware Edsim Models EDX x xlsx De IE x 11 6 File Edit View Insert Format Tools Data Windows Help X 12 7 E SE RI 13 8 F4 mg dl A B D E F G H K M 1 SIMULATION OUTPUT 16 11 2 17 12 18 13 3 Index Type Sys Tsim Tol C Ins C Glu C 19 144 mg L mU L mg dl B EM en 2 sso E 7 2 0 096 0 5 90 E a 22 17 Em Copy 8 3 Norm 0 144 0 5 90 23 18 T p E 4 Norm 0 192 0 5 90 Paste 25 20 10 5 Norm 0 24 0 5 90 Paste Special 6 Norm 0 288 0 5 90 26 21 Insert Cells 3 22 M12 7 Nor
6. User Guide MEDINWARE N C Punt May 2013 Edsim user guide N C Put 00 Date 16 09 2013 First print MEDIWARE Document History DOCUMENT HISTORY 1 02 16 09 2013 Corrected header MEDIWARE TABLE OF CONTENTS 1 TIN PRODUC TION Po m LLE DOCUMENT FP 2 POCCMNENTSCO calata EDRN Nail 2 INSTALLATION lla iaia 2 1 SYSTEM 1 2 6 6 re rece rioni 2 2 INSTALLATION EOLDER sissi ai 2 3 INSTALLATION PROCEDURE irrita ANSTALEJSICENSE LR easet auteni M PPM NE IE PI EI 3 3 1 2 MODEL 3 3 SIMULATE 000 0 0 0 3 4 MODIFY A MODEL ettore eee rice enemies se ese een ee 3 5 DECORATE MODEL 2 000000000 4 EDSIM Ali XOVERVIEUW alli Ack ADDING OBIO Silla 2 5 MANIPOLATINGOBIBCIS rire qup CONNECTING OB IBC TS cose aan 4 5 SELECTING MULTIPLE 8 20200 4 6 DUPLICATING AND DELETING SELECTED OBJECTS
7. 1 Tur 11 1 Sys Tsim 01 1 PostOn 2 Norm 3 Norm 4 Norm 5 Norm 6 Norm 7 Norm 8 Norm 9 Norm 10 Norm 11 Norm 12 Norm 13 Norm 14 Norm 15 Norm 16 Max 17 Norm 18 Norm 19 Norm 20 Norm 21 Norm 22 Norm 23 Norm 24 Norm 25 Norm 26 Norm 27 Norm 28 Norm 29 Norm 30 Norm 31 Norm 32 Norm 33 Norm 1 344 1 44 1 536 1 632 1 728 1 824 1 92 2 016 2 112 2 208 2 304 2 4 2 496 2 592 2 688 2 784 2 88 Chart Output 0 0 8 727217 15 88975 21 72933 26 45259 30 23608 33 2304 35 568392 37 3459 39 61271 40 24319 40 61715 40 78229 40 78229 40 77879 40 64042 40 39546 40 06754 39 07034 39 23817 38 70048 38 27233 37 76473 37 25098 36 73094 30 22720 35 72558 35 23469 34 756698 34 2931 33 84498 Formulas T gt 1 rm d rt G H l C02 C mg L ol 0 0 0 0 085938 0 320868 0 674565 1 121637 1 640805 2 214304 2 827348 3 46769 4 125233 4 791699 5 460349 6 125745 6 783536 6 783536 7 430292 8 063347 8 680073 9 280776 9 862599 10 42545 10 96892 11 192856 11 99729 12 48241 12 94852 13 39603 13 82541 14 23718 14 63191 15 01017 15 37257 Data 0 00 Review General LIO 3 0 Number C03 C mg L 0 0 0 0 170768 0 633395 1 322642 2 184153 3 172818 4 251375 5 389205 6 56131 7 747429 8 931288 10 09996 11 24334 12 35363 12 35363 13 42501 14 45324 15 43542 16 36973 17 25523 18 0917
8. 15 87948 19 61935 20 31245 20 96019 21 56414 22 64774 23 13106 23 57 793 23 99022 24 3698 Microsoft Excel View Styles 04 mg L 0 0 0 0 254505 0 937822 1 945377 3 190962 4 603889 6 126558 7 712378 9 323997 10 9318 12 5126 14 04861 15 520643 16 93637 16 9363 18 27189 19 52612 20 70335 21 79004 22 00852 23 74046 24 59471 25 37406 20 08171 20 72114 27 29598 27 800999 28 2669 26 6 046 29 02431 29 33199 29 59094 Observations Symbols Dill 4 42 Developer gra Insert ge Delete Format prr o m E 2 d 97 Sort amp Find amp C Filter Select Editing Team Cells al E MEDIWARE 9 1 9 2 9 3 9 4 FITTING MODELS TO OBSERVATIONS Adding Observations Selecting Parameters Adjust Settings Fitting Results 43 Programming Edsim MEDIWARE Programming Edsim 10 EDSIM PLUG INS 10 1 Monte Carlo Simulator 10 2 Dose Calculator 44 MEDIWARE Programming Edsim 11 PROGRAMMING EDSIM 11 1 Macros Edsim models can also be represented in the C programming language We refer to such models as macros Macros can be created from scratch within the Edsim application There is no need for a separate development environment like Visual Studio A default macro template is generated when you select New Macro from the File menu using System using System Ling usi
9. 22 0000201 AT OBIECT NAME TYPE NEEE Ao UOBIECPPROPERIE Sidia A9 LI ME ERROR MESIACE iaia 5 EDSINE MODELS S P ia a ie eat 52 ATEOORIDS Lalli io 23 3 SYMBOL C ATBEGOBIBS a sure 54 EDITING MODEL PROPERTIES 5 4 1 Obj Object sia 5 4 2 Var Variables cere rioni riesce ceci riorionioni 5 4 3 Par Parameters Tab ina 5 4 4 Pop Population Parameters Tab ii 5 4 5 Con Constans Filiali 5 4 6 ODICODHODBS ani 5 4 7 Obs Observations Tabiano 5 4 8 EVER 5 4 9 Sun Simulation TA 5 4 10 AGIO RR AR 5 4 11 ADD Applicaton TU usse 6 BUILDING MODELS cicsriir raii raii 6 1 ONE COMPARTMENT 6 2 TWO COMPARTMENT 6 3 AREA UNDER THE CURVE AUC esses eene Henne nennen nenas TIME ABOVE LEVEL pipa ieri cna cur atea rari 7 RESULTS VIEWER sorrisi EA RNEER ENE Table of Contents MEDIWARE Table of Contents 7 1 MICROSOFT EXCEL COMPATIBLE 2 000 00 10000000000 38 722 WORKBOOK DESIGNER MODE
10. 885514 6 187822 7 359853 8 417515 9 374653 10 24332 11 03402 11 75589 12 41691 13 02402 13 58328 14 09999 14 57876 15 02363 15 43813 15 82535 16 18799 16 52843 C03 C mg L 0 0 0 3 593346 6 735935 9 485308 11 89152 13 99811 15 84297 17 45907 18 87513 20 11613 21 20384 22 15724 22 99285 23 72509 24 36652 24 9281 25 41943 25 84885 26 22367 26 55028 26 83427 C04 C mg L 0 0 0 5 33813 9 908974 13 81573 17 14792 19 98317 22 38883 24 42326 26 1371 27 57422 28 77264 29 76533 30 58084 31 2439 31 77594 32 19549 32 51861 32 75917 32 9292 33 03907 33 09776 Click on the Model tab at the top The model appears again Symbols Debug 12 MEDIWARE Quick Start Now click on the Mini Charts button in the toolbar TPeripheral Qm b C04 C01 C03 TPeripheral Compartment TPeripheral 101 O01 TInjection TElimination This will show the curves concentration in the object compartment they are associated with thereby supplying the user with a spatial view Now double click the TInjection object 101 The object properties window will appear from the right side ice File Model Macro Object Help Name 101 Tlnjection inx gt OBJECT Name 101 Tinjection Substance 2 Molecular Weight Sync Object Interactant Dose Tnul Tdur Tint Ndos o
11. Only contains an image of the model The eds xml cs and dll formats can be saved and opened by Edsim All other formats can only be saved which makes them essentially one way tickets We refer to them as export only formats Only the Edsim native edx format is capable of storing graphical model layout information If you open xml cs or dll files a new layout will be automatically generated Format Selection In the file Save As dialog you can select the file format in the Save as type field Enter a file name select the desired format and click Save to store the model on disk The Open dialog works in the same way Save as type Edsim EDX File c EET Edsim C5 File cs Hide Folders Edsim AML file xml Edsm DLL file dil mm Edsim EXE file exe Visio VDX file dx Vector WMF file wrmf Bitmap PING file png Adobe PDF file pdf Excel XLS File xls Excel XLSX File xlsx 41 MEDIWARE 8 3 Excel Export Model Storage If you save a model in Excel xls x format Excel or any other default xls file handler will be automatically launched after the file has been saved to disk ni File amp Clipboard 05 Go _ jv A B C SIMULATION OUTPUT Model Home Calibri B I 0 PreOn Insert 11 U A A4 27 A Font Page Layout l emo05_Decoration xlsx fi UM M
12. The function of the toolbar buttons is explained here ad Mew Model Edsim File Model Macro Object Help Exit Edsim Open an existing model Create a new model clearing the existing model Save current model Copy a bitmap image of the current model or chart to the clipboard Build the current model or compile the current macro Simulate the current model Fit the current model Lay out model automatically E i 5 Zoom to fit Zoom in or out so that all model objects visible Cancel zoom Restore zoom to its original state 100 C Zoom in in steps of 1096 Zoom out in steps of 10 W Show or hide link numbers Show or hide mini graphs E 5 Assign an image to an object Menu Items Edsim Desktop Abort running simulation or fit procedure e g if it is taking too long to complete The following table lists all menu entries and their function Please note that the terms Macro model expressed as C source code and Object object expressed as C source code will be explained later in this manual 21 MEDIWARE Edsim Desktop New Model Create a new model Macro Create a new macro Object Model Create a new object Open Open an existing model from file Macro Object Model Open an existing macro from file Open an existing object from file Close Close current model Macro Close current model Obje
13. is used for generic tasks like addition and integration Patient A patient object is typically used for allometric parameter scaling We refer to the Edsim PKPD Library manual and video tutorials for a complete list and detailed description of all objects available in Edsim 24 MEDIWARE Edsim Models 5 3 Symbol Categories Symbols are the building blocks of an object and are used in equations defined within that object We discriminate between the following symbol categories Constants Event Constants Invariant symbols used in event equations Option Constants Invariant symbols used for setting object options Parameters Fittable Parameters Time invariant symbols that can be fitted Non Fittable Parameters Time invariant symbols that cannot be fitted Variables Interpolated Variables Time variant symbols that must interpolated Differential Variables Time variant symbols that must be integrated 5 4 Editing Model Properties 5 4 1 Obj Object Tab OBJECT Name 101 Code Tinfusion Substance Molecular Weight Sync Object Interactant LI Color L Dose Tnul Tdur Tint Hdos Here you can specify the name and molecular weight of the substance You can mark an object as being an interactant so that it can be discriminated from another object of the same type participating in an interaction Also the display color can be set here Objects can be synchronized to events occurring in other
14. library These objects are also programmed in C You can create a new object in Edsim by selecting New Object from the File menu You will be presented with an empty object template than can serve as a starting point for your own objects using Mediware Edsim ModLib namespace Mediware Edsim ModObj Description Edsim Object definition template public class TMyCompartment BCompartment Symbol declaration go here Pre connect initialization public override void Init 7 Post connect initialization public override void Final Normal Equations public override void CalcNorm Differential Equations public override void CalcDiff You must recompile the PKPD object library when you want to add a new or modified object to it You must then restart Edsim in order to use the updated library You can view the source code of any existing object in a model diagram by double clicking it You then click the Code button in the object tab Obj Below you see an example of the code for an injection object using Mediware Edsim ModLib namespace Mediware Edsim ModObj lt summary gt IV bolus injection input class lt summary gt Description IV bolus injection input class public class TInjection TInput lt summary gt Execute on event lt summary gt public override void EventoOn Ay Value Ay Value Dose Value
15. objects the synchronization object This sync mechanism is typically used to reset a calculated AUC or average concentration using events occurring in an input object Some objects support events A number of event sequences can be entered in the event table The timing of these sequences may overlap each other allowing for very complex time tables The example above represent an infusion dosing schedule in which 100 mg Dose is given at time 4 h Tnul for a duration of 1 h Tdur with an interval time of 8 h Tint In total 10 dosages are given Ndos These event values are considered to be a special kind of constants event constants 25 MEDIWARE Edsim Models 5 4 2 Var Variables Tab VARIABLES vii 5 Unit o 4 9 COLA COL C DO CO1 Cu OO The variables tab lists all the variables associated with the selected object Here you can change the initial value and the unit of the variable You can also mark variables as Observed Obs so that it is shown in the output chart The Axis property assigns the variable to the left y axis unchecked default or right y axis checked You can select a curve color for a variable when you click on the Color box A white color means that the colors are assigned automatically by Edsim i Color MURE TEGED RENON HENNEN RENT 11 METER ERE 77 TEENE 118 118 i i By increasing the object properties window size additional prope
16. tool and select the variables tab Var Mark variable AUC as observed and run a simulation 35 MEDIWARE Building Models C02 TPeripheral 001 TElimination 101 Tinjection X01 Tintegrator 6 4 Time Above Level Continue with the model from the previous paragraph Select the integrator tool and changes its type to TLevel Double click the level tool and select the variables tab Var Enter a value of 10 mg L for the LEVEL variable and uncheck its observed status Next check the observed status of the RTAL variable relative time above level TPeripheral NN NNNN nl C01 Compartme O01 TElimination 101 Tinjection TUE X01 TLevel The level tool is typically used for calculating the time above MIC t mic of antibiotic drugs 36 MEDIWARE Building Models 6 5 Effect Continue with the model from the previous paragraph Now drag an effect object on the desktop Connect peripheral compartment C02 with effect object E01 Double click the effect object and select the variables tab Var Mark variable E as observed and run a simulation eS C02 E01 TPeripheral TSigmoid C01 rt ompartme TElimination 101 X01 TLevel Double click the effect object again and select the parameter tab Par Enter a value of 1 mg L for the EC50 parameter and run a simulation again Note how the e
17. Aje MEDIWARE Edsim Models 5 4 10 Fit Fitting Tab FITTING Method Stop criterion Max iterations This screen displays all fitting settings like fitting method Simplex or Marquardt stop criterion and the maximum number of allowed iterations 0 means no limitation 5 4 11 App Application Tab DIAGRAM Desktop Ohjects Links LI PLOT X Variable Variable X Log scale Y Log scale L X Grid lines L Y Grid lines CJ EXPORT Start Excel Start Visio NE In the diagram section of the application tab the default color for the desktop objects and links can be specified Please note that the color for individual objects can be controlled in the object tab In the plot section the user can select which symbol is the x variable default Tsim and which symbol is the y variable default blank A blank entry for y variable means that all observed variables will be shown in the chart The user can also specify if an axis should be log scaled and if grid lines should be displayed In the export section the user can specify if the application supporting a particular export format should be automatically launched after the export has been completed do MEDIWARE Building Models 6 BUILDING MODELS 6 1 One compartment Model Start Edsim and drag the following objects on the desktop a compartment an input and an output C01 TCompartment O01 TElimination 101 TInjection
18. MEDIWARE Quick Start 3 QUICK START 3 1 Launch Edsim Double click on the Edsim icon on the windows desktop in order to start the application Edsim The application window will appear no9o0N 3 2 Open a Model Click on the File menu and select Open Model File gt Open gt Model or click on the open model button in the toolbar File gt Model gt Open Open Model Button File Model Macro Object Help e 24 MEDIWARE 3 3 Select the Demo edx file in the open file dialog and click Open aj Open 1211 Computer SYSTEM C Mediware Edsim Models EDX gt SD rr Organize New folder Ft Favorites Desktop 1 Groningen2013 l Downloads Prague2013 1 Dropbox _ Demo edx Google Drive S Recent Places i SkyDrive Desktop Libraries a Homegroup r ncpunt 1 Computer Ca Network GA Control Panel 2 Recycle Bin Wj Databases DotNet 12 Editors i Ramer Date modified 28 05 2013 15 27 28 05 2013 15 27 29 05 2013 20 12 File Model Macro Object Help OIGOSB O 5 it Simulate a Model Type File folder File folder EDX File Now start a simulation by clicking the Run button 11 Quick Start x JU gt d Select a file to preview X Type 88 2 MEDI
19. WARE Quick Start The progress of the simulation is displayed in the progress bar at the bottom A chart will appear after the simulation has been completed showing the concentration in all 4 compartments File Model Macro Object Help 50 Time h C01 C mg L C02 C mg L C03 C mg L 04 mg L M gt Chart Output Observations Symbols Debug Click on the Output tab at the bottom of the screen in order to view the simulation output as a table a9 C Mediware Edsim Models EDX De File Model Macro Object Help 6089 E 6000 O 00 our O teh i i i e e OW Pe 21 22 4 E 6 8 9 10 20 22 23 24 25 26 27 Type PreOn PostOn Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm Norm 4 Chart Output Observations Sys Tsim h 0 096 0 192 0 288 0 384 0 48 0 576 0 672 0 768 0 864 0 96 1 056 1 152 1 248 1 344 1 44 1 536 1 632 1 728 1 824 1 92 C01 C 1 0 100 100 91 03348 83 22171 76 41312 70 47607 65 29626 60 77442 56 82436 53 37122 50 34999 47 7042 45 38481 43 34925 41 56051 39 98645 38 59918 37 37444 36 29116 35 33105 34 4782 33 71881 C02 C mg L 0 0 0 1 814193 3 434643 4
20. and change the Mode option from Rate to Clearance Now select the parameters tab Par again Note how the rate constant 1 h has been replaced with clearance CL L h PARAMETERS 8 Value Sdev _ OOLCL 50 0 OE Many Edsim objects support this feature of switching between rate and clearance mode 34 MEDIWARE Building Models 6 2 6 3 Two Compartment Model Continue with the 1 compartment model from the previous paragraph Drag another compartment on the desktop C02 TPeripheral x 7 NN N O01 TElimination 101 TInjection Please note that the 2 compartment is automatically created as a peripheral compartment Now connect compartment C01 source with compartment C02 target and run a simulation C02 TPeripheral O01 TElimination N 101 Tinjection Note that the connection between the central compartment C01 and the peripheral compartment C02 is bidirectional which means that material can flow in both directions However it is important to realize that formally C01 is still is the source object and C02 still the target object even though the connection is bidirectional Area Under the Curve AUC Continue with the 2 compartment model from the previous paragraph Now drag a tool object on the desktop Connect compartment C01 with the integrator tool X01 Double click the integrator
21. are organized in a matrix in which the first column represents the observation time Subsequent columns hold the values for a particular variable which can be selected on the top row of the table You are completely free where to enter your data in the table In the following example first the values for C01 C were entered Then a second table with C01 Cu values was added 28 MEDIWARE Edsim Models OBSERVATIONS mg L mg L Now if you leave the observations tab by clicking on another tab e g object tab and come back again to the observations tab you will see that all observations have been sorted Simply leave cells blank on time points where you do not have a variable value 5 4 8 Ext Externals Tab EXTERNALS Name External Name O01 Ax A i OUO1 Vx V 29 MEDIWARE Edsim Models 5 4 9 The externals tab lists all the externals associated with the selected object Externals are symbols that are required by an object but are defined in another object So the list of external symbols represents the interface of an object The previous example shows the externals of a TElimination output object 001 This elimination object requires the amount A and volume V symbols of a connected source compartment Within the elimination object these symbols are referenced as Ax and Vx In this example the external name is fixed and cannot be changed by the user The following example shows the externals of a TIntegrator tool obj
22. ct Model Close current object Save Save current model to file using the existing name Macro Object Model Save current macro to file using the existing name Save current object to file using the existing name save As Save current model to file using a new name Macro Object Model Save current macro to file using a new name Save current object to file using a new name Print Print current model Results Print current results set Restart Restart Edsim required after a library build Exit Ext Edsim Build Build the current model Convert to Macro Convert the current model to a macro C source Run Build and simulate the current model F Build and fit the current model mE Insert Object Build Insert object declaration into macro C code Compile the current macro Convert to Model Convert the current macro to a model Build and simulate the current macro JJ C 3 Fit Build and fit the current macro Build Build Library Compile the current object Build library by compiling all available objects Restore Library Restore the factory default library About Edsim Show version and license information 22 MEDIWARE Edsim Desktop 4 11 Error Messages Error messages are displayed in a window at the bottom of the desktop Click on some free space on the model desktop or on the button to hide this window again A complete list of possible error messages
23. e and type automatically when you add or duplicate an object Mame 01 ype TCompartment T Compartment TPeripheral TPortal TSink TVirtual TVirtualLinked AGlucose Alnsulin AlnsulinEx 19 MEDIWARE Edsim Desktop 4 8 Object Properties Double clicking an object brings up the object properties window from the right side Clicking the the button hides this window again Double clicking on some free space on the model desktop toggles the visibility of this window Name 101 Tinjection inx gt OBJECT Name Type Tinjection Substance Molecular Weight Sync Object Interactant L Color Dose Tnul Tdur Tint Ndos The tabs in object properties window represent different categories of properties Obj Object dosing sequences e Var Variables select which variables must be observed during a simulation e Par Parameters select which parameters must be fitted during a fit e Pop Population parameters used in Bayesian estimation e Con Constants constant symbol values e Opt Options named symbol values e Obs Observations measurement values that can be fitted e Ext Externals constitute the interface between objects e Sim Simulation settings simulation method e Fit Fit settings fit method e App Application settings plot colors etc 20 MEDIWARE 4 9 4 10 F Toolbar Buttons
24. ect Here the user is free to change the externally referenced symbol name used for integration EXTERNALS Name External Name XUT M Sim Simulation Tab SIMULATION PRIMARY Duration Resolution Integration method SECONDARY Fixed step size Adaptive step factor Integration accuracy Peak Level accuracy Peak detection Level detection OUTPUTS Normal outputs Observation outputs Event outputs IS ISI ESI P PROFILING Use profile Event object Profile variable Ttrough Tpeak 30 MEDIWARE Edsim Models This screen displays all simulation settings In the primary section the simulation duration resolution and integration method can be specified Edsim will establish a simulation duration automatically when a value of 0 is entered here The automatically derived simulation duration is based on the number of events and event time interval In the secondary section more low level simulation settings can be specified These settings directly control the integrator which is used for solving the differential equations In the outputs section the user can specify when the simulator should generate an output value Normal outputs are driven by the selected simulation resolution Observation and event outputs are triggered by the occurrence of an event or observation at a particular time The profiling section contains t
25. en a source object and a target object You can connect objects by clicking on some free space in the source object and start dragging the mouse to some free space within the target object The sign is shown if a connection cannot be made in a particular context E g the direction of the link can be incorrect or the source and target may be incompatible 7 MEDIWARE 1 Click on source 2 Start dragging 3 Drag to target 4 Release button Incorrect Direction Incompatible Objects 18 Edsim Desktop MEDIWARE Edsim Desktop 4 5 4 6 4 7 Selecting Multiple Objects Select an object by clicking on some free space within the object boundaries Repeat this process for other objects with the Ctrl key pressed in order to select multiple objects You can also select multiple objects by dragging a box around the objects Duplicating and Deleting Selected Objects Select one or more objects and press one of the following buttons on the toolbar 4 Duplicates selected objects including property values The new and original objects will be automatically linked if they are compatible e g TSink Delete selected objects Object Name amp Type The object name and type of the currently selected object is displayed in the toolbar at the top of the screen You can give the object a new name or change its type An object must have a unique name among all the objects on the desktop Edsim will generate a nam
26. ffect levels have increased C02 E01 TPeripheral TSigmoid C01 Compartme O01 TElimination 101 X01 TLevel d MEDIWARE Results Viewer 7 RESULTS VIEWER 7 1 Microsoft Excel Compatible Workbook The results tab of Edsim is in fact a fully featured spreadsheet that is 100 compatible with Microsoft Excel 00 File Model Macro Object Help Model Macro Results 180 Tol C mg L Ins C mU L Glu C mg dL Time h 4 Chart Output Observations Symbols Debug Ready File Model Macro Object Help Sys Tsim Tol C Ins C Glu C h mg L mg dl 0 Norm 0 90 1 Norm 0 048 90 2 Norm 0 096 90 3 Norm 0 144 90 4 Norm 0 192 90 5 Norm 0 24 90 6 Norm 0 288 90 7 Norm 0 336 90 8 Norm 0 384 90 9 Norm 0 432 90 10 Norm 0 48 90 11 Norm 0 528 90 12 Norm 0 576 90 13 Norm 0 624 90 14 Norm 0 672 90 15 Norm 0 72 90 16 Norm 0 768 90 17 Norm 0 816 90 18 Norm 0 864 90 19 Norm 0 912 90 20 Norm 0 96 90 21 Norm 1 008 90 27 22 Norm 1 056 90 4 M Chart Output Observations Symbols Debug Ready U o oo oo ooo o oo o Un Ui Ur
27. he settings for the profile simulation mode In this mode additional outputs can be generated at particular time points These additional values are outputs at Ttrough Tpeak and Tmax Ttrough and Tpeak outputs also require the observation outputs setting to be checked Also an event object and profile variable must be specified Below is a typical setup for a profile simulation in which only the normal outputs have been disabled OUTPUTS Normal outputs L Observation outputs I Event outputs PROFILING Use profile lv Event object Profile variable Ttrough Tpeak This yields the following results in a 4 compartment model with extravascular administration dosing interval time is 8 hours over a period of 2 dosing intervals A B C D E F G H 1 SIMULATION OUTPUT _3 Index Type Sys Tsim 01 C02 C C03 C C04 C m h mg L mg l mg l mg l 2 O PreOn 0 0 0 0 0 6 1 PostOn O O 0 0 0 Fi 2 Obs 0 5 30 9204 1 756336 3 391213 491376 8 3 1 248 40 78229 6 783536 12 35364 16 93637 4 Obs 7 5 24 32637 2247757 26 23317 26 33266 10 5 8 23 848574 22 63016 25 84233 25 74702 11 6 PostOn 8 23 84874 22 63016 25 84233 25 74702 La 7 54 31862 24 418049 28 829655 30 10 03 13 amp 9 216 63 53834 29 33 5 36 83787 40 92598 14 9 Obs 15 5 42 81409 43 32859 46 3659 45 88368 15 10 PreOn 16 42 04574 43 24218 45 64956 44 98277 16 11 PostOn 15 42 04574 43 241715 45 64956 44 98277
28. ilio cata iii inn 47 V MEDIWARE Introduction 1 1 1 2 1 3 INTRODUCTION Document Purpose This document is the Edsim user guide It shows the user how to design and run basic PKPD models using Edsim Advanced modeling examples are given in the accompanying video tutorials http Awww mediware cz Documents Scope This document is limited to describing the basic operations in Edsim It does not represent an advanced PKPD modeling instruction Edsim Mission Edsim is an object oriented visual pharmacokinetic pharmacodynamic modeling tool for use in education and research Edsim discriminates itself from other PKPD modeling software for the following reasons Edsim is not a universal modeling tool that can be used in multiple application domains Instead Edsim focusses on PKPD modeling applications This clear unambiguous choice resulted in a very easy to use yet powerful application Edsim can be used for a broad range of PKPD modeling problems The Edsim PKPD object library can be extended by the end user library The Edsim application can be extended by programmers plug ins Edsim is very suitable for use in research and education MEDIWARE Installation 2 1 2 2 2 3 Installation System Requirements Edsim requires the Microsoft NET framework version 4 0 to be installed on your system You can download this package at www microsoft com download Installation Folder Y
29. in GUI elements 1 Model desktop 2 Object properties category tab is 8 3 Error messages 4 Object templates can be dragged to the model desktop 5 Main menu 6 Tool bar 7 Model view tabs model diagram result data and plug ins 8 Object property category tabs a Obj Object b Var Variables c Par Parameters d Pop Population parameters e Con Constants f Opt Options g Obs Observations h Ext Externals i Sim Simulation settings j Fit Fit settings k App Application settings plot colors etc 46 MEDIWARE Edsim Desktop 4 2 4 3 4 4 Adding Objects You can add objects to a model by dragging an object template on the desktop Release the left mouse button at the position where you want to place to object ai Edsim uL New Model Edsim l File Model Macro oJ Edsim File Model Macro File Model Macro 1 Select the template 2 Drag it on the desktop 3 Release the mouse button Manipulating Objects You can conduct three basic operations with an object move resize and connect see diagram below Move object Resize object Connect object Anchor points appear when you select an object Click and drag the center anchor point in order to move the object Click and drag one of the outer anchor points in order to resize the object Click and drag on some free space within the object to initiate a connection Connecting Objects Connections are links betwe
30. ional icons Create a desktop icon Review your installation settings Click Back to modify these or click Install to continue Setup Edsim Completing the Edsim Setup Wizard Setup has finished installing Edsim on your computer The application may be launched by selecting the installed icons Click Finish to exit Setup Launch Edsim You can directly launch Edsim after the installation has been completed MEDIWARE Installation 2 4 Install License Edsim will stop working after a 30 days trial period You must purchase a license in order to continue using Edsim The Edsim about screen is automatically shown when the trial period has expired Product Information Edsim Version 1 0 0 3 Copyright 2013 Mediware a 5 Client Information Company Unregistered First Name Unregistered Last Name Unregistered Hardware ID BB3D S8DA0 C 00 25E1 EB6A 6 5D License Information License Type Trial license Expiration Date 11 23 2012 Expired Licensed Plugins Install License Copy Hardware ID Email the displayed Hardware ID to the vendor Simply click Copy Hardware ID and paste it into your email program The license file will be send to you by email as an attachment Save this attachment to disk and click the Install License button in Edsim Select the license file and click Open Now you will have a licensed copy of Edsim so that you can continue using it
31. is given in Appendix 12 1 cal New Model Edsim File Model Macro Object Help Platform Microsoft Windows NT 6 1 7601 Service Pack 1 AMD64 UnresolvedSymbolException Symbol Ax in object C82 has not been resolved by any of the connected objects Objects may be incompatible or links missing An attempt to start a simulation in the example above will result in an error message because the TPeripheral object was not linked to the TCompartment object 229 MEDIWARE Edsim Models 5 1 5 2 EDSIM MODELS Model Structure The generic structure of a model is displayed below A model consists of one or more objects each object representing a particular PKPD process e g absorption distribution or elimination In turn each object is built of a number of symbols These symbols used in the PKPD equations Object 1 Symbol 1 Object 2 Symbol 2 Object 3 Symbol 3 Object N Symbol N Object Categories Edsim objects are the building blocks of a model We discriminate between seven different object categories a Compartment compartment is a container for a material substance drug o Input An input introduces new material in a compartment gt Output An output removes material from a compartment wy Transfer A transfer moves material from a source to a target compartment gt Effect An effect is calculated from a concentration in a a Tool A tool object
32. m 0 336 0 5 90 nsert Cells Ready 14 9 Norm 0 432 0 5 90 Clear Content M 15 10 Norm 0 48 0 5 90 16 11 Norm 0 528 0 5 90 Insert Comment 17 12 Norm 0 576 0 5 90 18 13 Norm 0 624 0 5 90 To 19 14 0 672 0 5 90 Find and Replace 20 15 Norm 0 72 0 5 90 Range Explorer 21 16 Norm 0 768 0 5 90 Workbook Expl 22 17 Norm 0 816 0 5 90 sosia cei 23 18 Norm 0 864 0 5 90 Workbook Designer h 24 19 N 0 912 0 5 90 2 anom Hyperlink 25 20 Norm 0 96 0 5 90 26 21 Norm 1 008 0 5 90 SpreadsheetGear 4 ncc n nn ad 4 Chart Output Observations Symbols Debug Ready i In the external results viewer you have now full access to the spreadsheet menu Please note that both viewers remain in sync with each other If you type something in one spreadsheet it will also appear in the other one and vice versa Dual Monitor Support We can use the workbook designer mode of the results viewer for the creation of a dual monitor setup Move the Edsim application window to the left monitor Select the model tab and maximize the application window Now move the copy of the results view designer mode to the right monitor Select the chart tab and maximize the window 39 MEDIWARE Results Viewer E a New Model Edsim File Model Macro Object Help 000 AAR Name gt xme 00D c02 TPe
33. ng Mediware Edsim ModLib using Mediware Edsim ModObj using Mediware Edsim ModWrk using Mediware Edsim ModSim using Mediware Edsim ModFit namespace Mediware Edsim Model public class TUserModel TWorkModel f Input public TInjection I1 new TInjection f Output public TElimination 01 new TElimination Compartments public TCompartment Cl new TCompartment Connect objects public override void Connect Link I1 C1 Link C1 O01 Pre connect initialization public override void Init Il A amp ddEvent l100 0 0 8 10 Post connect initialization public override void Final Simulator initialization public override void InitSim SimSet settings jf Pitter initialization public override void InitFit FitSet settings The model above is a simple 1 compartment model with an injection input and an elimination output The injection object defines an event sequence of 10 times 100 mg every 8 hours You can use this as a starting point when building your own models in C As an alternative you can also convert an existing model diagram into a macro by selecting Convert to Macro from the Model menu You can use this feature to learn of complex models can be represented in C 45 MEDIWARE Programming Edsim 11 2 Objects In model diagrams and macros you make use of existing PKPD objects which are part of the Edsim PKPD object
34. ou can install Edsim on any folder on your system This can also be a USB memory stick Installation Procedure Double click the Edsim setup program The setup language selection dialog will appear A Select the language to use during the p RT installation Select the language and click OK Welcome to the Edsim Setup Wizard This will install Edsim 1 003 on your computer It is recommended that you dose all other applications before Click Next to continue or Cancel to exit Setup Click Next to continue MEDIWARE Installation 4 Setup Edsim Select Destination Location Where should Edsim be installed Setup will install Edsim into the following folder To continue dick Next If you would like to select a different folder dick Browse C Mediware Edsim At least 54 4 MB of free disk space is required Specify the destination location and click Next 05 Setup Edsim Which additional tasks should be performed j Select the additional tasks you would like Setup to perform while installing Edsim I Create a desktop icon Specify if you want to have a desktop icon recommended and click Next MEDIWARE Installation Setup 5n MEME e Ready to Install Setup is now ready to begin installing Edsim on your computer Click Install to continue with the installation or dick Back if you want to review or change any settings Destination location C Mediware Edsim Addit
35. pression is given below BWpop This can be simplified if Factor 1 and Bwpop 70 kg We added the units between square brackets for the sake of clarity Bw k V L VIL mrs Finally we can rearrange this to the classical denormalization formula V L V L 70kg Bw kg 27 MEDIWARE Edsim Models 5 4 4 5 4 5 5 4 6 5 4 7 Pop Population Parameters Tab POPULATION Name The population parameters tab lists the same parameters as the parameters tab However in this screen the parameter population values and population standard deviations can be entered These values are used with Bayesian estimation Con Constants Tab CONSTANTS Name Unit COl fu The constants tab lists all the constants associated with the selected object Here you can change the value and unit of the constant In the example above the constant fraction unbound fu for compartment 01 is displayed Opt Options Tab OPTIONS Name PO1 Mode PO1 Prefit POl Race POl RFunc 1 5 The options tab lists all the options associated with the selected object Options are special kind of constants in which the values are associated with a name The can be regarded as so called enumerations The example above lists all options associated with a patient object Obs Observations Tab The observations tab lists all the observations associated with the selected object Observations
36. r SteadyStateAbortException The simulation was aborted because steady state was reached LevelDetectException Level detection is enabled without setting a trigger variable SmallStepException Step size of s too small at time t 47
37. ripheral 101 001 Tinjection TElimination LEFT ran j al File Edit View Insert Format Tools Data Windows Help ings 16 Chart Area Y C01 C mg L C02 C mg L 50 Time h M 4 gt if Chart Output Observations Symbols Debug RIGHT The advantage of this dual monitor setup is that you can now see two chart types simultaneously On the left monitor you see the model with a spatial chart view while on the right monitor you see the combined chart view 40 MEDIWARE Model Storage 8 1 8 2 MODELS STORAGE File Formats Edsim supports a number of different file formats for storing models The following table shows which file formats you can save and or open with Edsim Ext stands for file extension Default Edsim format XML Includes layout and graphics Bare model format XML Like edx but without layout and graphics Source code model format C Same data as xml format Binary library model format NET Same data as xml format Binary executable format NET Requires MS Excel to run Excel BIFF xls or XML xlsx format Includes image charts and data TT Visio XML format Only contains a diagram of the model Windows Meta File format Only contains a picture of the model Portable Document Format Only contains a picture of the model B Portable Document Format
38. rties are revealed Here you can enter the population value of the variable Variable population values are used for allometric scaling of parameters see next paragraph VARIABLES 2 oO P Name Value Unit O q uU Population Unit COLA mg colc mg L 1 OOO mg L 26 MEDIWARE Edsim Models 5 4 3 Par Parameters Tab PARAMETERS mn gt 0 Name Value Sdev Unit COl V D E parameters tab lists all the parameters associated with the selected object Here you change the value standard deviation and unit of the parameter Check the Fit box if you want to estimate the parameter during fitting Check the Log box to indicate that the parameter is log normally distributed used in Monte Carlo simulations By increasing the object properties window size additional properties are revealed Here you can select the symbol used for allometric scaling of the parameter Also an allometric scaling factor can be specified Finally the display format for the scaled unit can be entered 0 1 2 or 3 PARAMETERS o E Value Sdev Unit cs Scaler I Unit 01 1 00 o L 01 B 1 3 L 700kgBw Below are the units from this example using different format values 0 L kg 1 L kgBw 2 L 70kg 3 L 70kgBw In this example the volume of distribution V is scaled using the patient body weight Bw The generic scaling ex
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