Either load simulation in a MoBi® that contains the standard structure of a ... Once done, export the simulation to MoBi® by right-clicking on the simulation name ...
Open-Systems-Pharmacology.org
Extending spatial structures in MoBi® Supplement to “Applied concepts in PBPK modeling: How to extend an Open Systems Pharmacology model to the special population of pregnant women” André Dallmann, Juri Solodenko, Ibrahim Ince, Thomas Eissing
1) Open a model that has to be structurally extended • •
Either load simulation in a MoBi® that contains the standard structure of a human individual Or follow the steps below to import a simulation that contains the standard structure of a human individual from PK-Sim® to MoBi®: • Open PK-Sim® and create a very basic simulation with standard European adult women, an arbitrary compound, and IV bolus administration. • Leave all parameters on default. • Once done, export the simulation to MoBi® by right-clicking on the simulation name and selecting “Send to MoBi…” as shown below
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2) Save a standard organ as .pkml •
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Adding a new (blank) container for every organ to be included, would require to add and define every parameter of this organ. A faster way is to save an existing standard organ1, e.g. Heart, as container and to reimport thereafter.
a standard organ is here defined as a solid organ that receives blood from the arterial blood pool and has a blood outflow to the venous blood pool Page 3
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3) Import the saved organ as container
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3) Import the saved organ as container • •
In the appearing dialog chose all container to be loaded. If a warning message appears thereafter, click OK.
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3) Import the saved organ as container •
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Rename all 3 Neighborhoods of the sub-compartments; these are in particular: • Neighborhood between Plasma (pls) and Blood cells (rbc) • Neighborhood between Plasma (pls) and Interstitial (int) • Neighborhood between Interstitial (int) and Intracellular (cell) In the example shown below, the “Myometrium” is added as new compartment and the neighborhood between Plasma and Interstitial is renamed by substituting Heart with Myometrium
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3) Import the saved organ as container • •
In the tab “Tree”, the imported new organ is now shown at the end of the organ list under the name Myometrium (or any other name that has been chosen for the new organ) In the “Properties” tab of the organ, change the description from Heart to Myometrium
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4) Wire the new organ to the circulatory system • •
In the diagram view, move the new organ to the bottom of the model structure via drag & drop and open it by clicking on the + sign at the top-left corner Right-click in the empty space of the model structure and select Show All Children to display other organ compartments
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4) Wire the new organ to the circulatory system •
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To create a neighborhood between two containers (e.g. between Myometrium|Plasma and VenousBlood|Plasma), hover with mouse cursor over the edge of a container and draw the appearing line to the edge of another container. Name the neighborhood according to the containers involved.
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4) Wire the new organ to the circulatory system •
Create neighborhoods for all connections between the new organ and the arterial and venous blood pools, i.e. in this example between: • ArterialBlood|Plasma and Myometrium|Plasma (“ArterialBlood_pls_Myometrium_pls”) • ArterialBlood|BloodCells and Myometrium|BloodCells (“ArterialBlood_bc_Myometrium_bc”) • Myometrium|Plasma and VenousBlood|Plasma (“Myometrium_pls_VenousBlood_pls”) • Myometrium|BloodCells and VenousBlood|BloodCells (“Myometrium_bc_VenousBlood_bc”)
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5) Define the partition coefficient interstitial/water • •
The partition coefficient (interstitial/water) is not included in the new organ imported in MoBi®; this parameter is by default never imported and has to be manually defined. To define it, go to the Tree tab Æ Neighborhoods Æ Neighborhood between interstitial and intracellular of new organ (here: Myometrium_int_Myometrium_cell) at the end of the list Æ MoleculeProperties Æ Parameters tab on the upper right Æ click on Add Parameter
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5) Define the partition coefficient interstitial/water •
Define the parameter exactly as shown below (adjust it to the name of the new organ, in case another name than Myometrium has been chosen) and click on “OK”:
The parameter to be added is called “Partition coefficient (interstitial/water)” and the variable “k_int_pls” is the partition coefficient between interstitial and plasma. Do not mix them up when specifying the path of “k_int_pls”. Page 12
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5) Define the partition coefficient interstitial/water •
The new formula for the partition coefficient (interstitial/water) appears now in the list of formulas under the name that has been used for the formula:
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7) Update body weight sum parameter – only necessary in older versions of MoBi® – •
Include the weight of the new organ in the sum formula for calculation of total body weight
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8) Update plasma volume sum parameter •
Include the weight of the plasma volume of the new organ in the sum formula for calculation of total plasma volume:
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9) Update lung blood flow sum parameter •
Include the blood flow (BF) of the new organ in the sum formula for calculation of cardiac output (= blood flow of the lung):
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10) Verify that tags for mass transport processes via the blood flow are set •
In the non-pregnant standard model structure, transport processes via the blood flow are defined per default for blood flows from the arterial blood pool to an organ and from the organ to the venous blood pool, if the there is a neighborhood defined between the Plasma (“Pl”) and BloodCells (“RBC”) of the organ and those of the arterial and venous blood pools, respectively:
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10) Verify that tags for mass transport processes via the blood flow are set •
Verify that the tag of the new organ is correct (all organs with the tag „ TissueOrgan“ receive blood from the Arterial Blood Pool and have a blood outflow to the Venous Blood Pool, if neighborhoods are drawn as described before)
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10) Set up a simulation • •
Now, a simulation can be set up and the concentration of a drug can be simulated in the new compartment. Note: When the simulation is set up, exclamation marks will appear for the molecule start values and parameter start values in the simulation. The reason for that is that the spatial structure building block now contains a new organ (here: Myometrium) with new parameter values (e.g. volume, blood flow, tissue composition, etc) and new molecule values (e.g. expression of enzymes) that are used in the simulation, but are not present in the molecule start values and parameter start values building block. To update the latter building blocks right-clicking on the building blocks in the simulation and select “Commit to building block …”
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