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Usage

The Certara.SimcypVBE package contains an example SimcypTM V23 workspace file PP1M_150mg.wksz for Paliperidone Palmitate and an observations data file PP.xml. After installing the Certara.SimcypVBE package, the files will be available inside your R library folder, in the subfolder Certara.SimcypVBE/examples.

To identify your R library folder, run the .libPaths() command from R. The first path will likely be your R user library, and the second path your R site library.

Pro-tip, you can open any folder location in R using the browseURL() command.

browseURL(paste0(.libPaths()[1], "/Certara.SimcypVBE/examples"))

In the next step, we will copy these files into a separate folder (e.g., your working directory in Pirana).

Run Simcyp VBE from Pirana

In Pirana, navigate to the folder where the example files have been copied. This is considered your “Pirana root directory”, and while not required, it is best practice to have any files used in your analysis saved inside this folder (e.g., the wksz and xml files).

Next, ensure that you are in the vbe context menu and have All folders selected.

Then, select Models > New Model (or use the shortcut Ctrl + n) to launch a Pirana dialog to select the example files for the VBE analysis.

Select the location of the wksz and xml files. Finally, select the “Create” button to launch the Shiny application.

Generate reference group results

The initial simulation with the supplied wksz file is often assumed to be the “reference group”. To simulate with given inputs supplied in the original wksz, navigate to the Simulate top level menu, and select the “Simulate” button in the left sidebar.

Note: The observation data points from the xml file will be visible in the plot, even if no simulation has yet been performed.

Next, ensure the “Virtual Population” radio button is selected (optionally edit the number of subjects from the default value of 10). Finally, ensure the “Reference” radio button is selected, then select the “Run” button to run the simulation.

Navigate to the Results > Virtual Population tab to visualize results.

Perform sensitivity analysis

For the Paliperidone example PP1M_ 150mg.wksz, the key inputs in the Shiny application to vary for sensitivity analysis include the Polydispersed Particle Size Distribution (PSD), which is in the Formulation Index subsection of Substrate > Absorption.

Navigate to this section in the Shiny application and enter a comma separated list of values or a sequence statement e.g., seq(0.1,0.9, 0.1) as illustrated in the inputs below.

Next, navigate back to the simulate tab - you will see an expanded grid of all parameter combinations given the input values you have entered.

Select the “Simulate” button in the left side bar and select the “Sensitivity Analysis” radio button. This perform simulation for a representative subject in the population, for each iteration of the unique parameter combinations.

Navigate to the “Results” tab in the left side bar and preview sensitivity analysis results from the “Sensitivity Analysis” tab.

You can select a row in the table below for a given iteration to observe the best fit through the data.

Generate test group results

Next, we will perform a virtual population simulation for our test group using Iteration 9 of our parameter combinations. We can select the “Simulate” button in the table for the given row, or, select the Simulate button in the left sidebar as we did previously.

Ensure that the “Test” radio button is selected, and that you have selected the correct iteration in the table that you want to use for the simulation. Finally, select “Run”.

Navigate back to the “Results” tab in the left sidebar and select the “Virtual Population” tab to view new simulation results for the test group. Select “Save & Exit” to close the Shiny application and return to Pirana.

Click the “refresh” icon in Pirana and you will see that the vbe output folder has been attached to the vbe model object in the Pirana table. Additionally you will see that the {vbe_name}_reference_group.csv and {vbe_name}_test_group.csv files have been copied to the Pirana root directory and renamed.

Note: These files are additionally available inside the simcyp_vbe_output_{n} subfolder with a timestamp, allowing you to create multiple test/reference combinations inside the Shiny app for exploration, however, only the last generated files are copied to the Pirana root directory and renamed accordingly e.g., {vbe_name}_reference_group.csv and {vbe_name}_test_group.csv.

Navigate to the Pirana scripts tab, with the {vbe_name} selected in the Pirana table (also ensuring that the corresponding {vbe_name}_reference_group.csv and {vbe_name}_test_group.csv files are indeed available in the Pirana root directory as visible in above screenshot), you can double click a script name or right-click > run script to generate the corresponding plot output.