Open Systems Pharmacology
ForumSetup
v10
v10
  • Introduction
  • Open Systems Pharmacology Suite Manual & Copyright
  • How to Contribute
  • Mechanistic Modeling of Pharmacokinetics and Dynamics
    • Modeling Concepts
      • PBPK Modeling - Systems Biology
      • PK and PD Modeling
      • Principles of PBPK Modeling
      • Expression Data for PBPK Modeling
      • Modeling of Proteins
      • PD and Reaction Network Modeling
  • Open Systems Pharmacology Suite
    • Modules, Philosophy, and Building Blocks
    • Getting Started
  • Working with PK-Sim
    • PK-Sim Documentation
      • Quick Guide‌
      • Options
      • Projects
      • Creating Individuals
      • Creating Populations
      • Expression Data
      • Compounds: Definition and Work Flows
      • Compounds: Defining Inhibition/Induction Processes
      • Administration Protocols
      • Events
      • Formulations
      • Simulations
      • Importing and Exporting Project Data and Models
      • Conversion of Projects from Previous Version
      • Command Line Interface - CLI
  • Working with MoBi
    • MoBi‌ Documentation
      • First Steps
      • The Building Block Concept
      • Model Building and Model Components
      • Setting up a Simulation
      • Simulation Results
      • Diagrams Overview
      • Tools
      • Reuse of Project Information from Previous Versions
  • Shared Tools and Example Workflows
    • Features of Tables
    • Chart Component
    • Comparison of Building Blocks
    • Parameter Identification
    • Sensitivity Analysis
    • Import and Edit of Observed Data
    • Default, Display and Base Units
    • Reporting
    • Working Journal
    • History Manager and History Reporting‌
    • Setting up a Reaction Network‌
    • Setting up a Drug-Drug Interaction in PK-Sim‌
    • Qualification‌
  • Working with R‌
    • ospsuite-R Documentation
  • Appendix
    • Appendix
    • OSP Suite Fact Sheet
  • References
    • References
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  1. Shared Tools and Example Workflows

Setting up a Drug-Drug Interaction in PK-Sim‌

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Last updated 3 years ago

Inhibition of a metabolizing enzyme or transporter by a drug can be defined directly in PK-Sim® in a simple and user-friendly manner. In the example workflow below, a drug-drug-interaction (DDI) model is set up using preconfigured templates compounds, e.g. the drug itraconazole, its metabolite hydroxy-itraconazole, and midazolam.

Load the predefined compound from templates into PK-Sim® by clicking on the Compound icon in the Load Building Blocks menu of the Import/Export tab.

In this case, the preconfigured itraconazole compound building block is imported.

In the predefined compound Itraconazole, Hydroxy-Itraconazole is already pre- specified as primary metabolite. However, users can make changes to all fields if desired and well-founded.

Process type and Ki values of the inhibition have already been pre-specified for the template compounds Itraconazole and Hydroxy-Itraconazole:

Next, expression levels of metabolizing enzymes can be added to the Individual building block to be used in the simulation:

Further building blocks can be defined in the respective sections and a simulation is then created by clicking on the Create button in the Simulation section in the Modeling and Simulation tab.

In the pre-configured compound templates, the inhibition processes for each enzyme or transporter are predefined, but can be adjusted by the user if applicable. Enzymes present in the Individual building block are matched with processes specified in the used Compound building blocks and metabolites are defined. Also, systemic processes regarding transport or excretion (e.g. ‘Glomerular Filtration’ like in the example displayed here) are shown and can be modified as desired.

In the next step, application protocols for each compound are defined using the available building blocks the user has configured before.

After having added and matched all building blocks required, the simulation is set up and can be run by either hitting F5 or using the Run button in the Simulation section of the Modeling and Simulation tab.

After running the simulation, all compounds and metabolites (in this case Itraconazole, Hydroxy-Itraconazole and Midazolam) can be plotted and the simulated PK data can be analyzed for each.

Also, at any given time after the simulation has been created, the simulated metabolic network that was defined can be displayed as a reaction diagram. Like in MoBi®, the blue dot of the reaction triangle connects to the educts of the reactions, the red dot to catalysts (e.g. interacting substances, enzymes or transporters) and the green dot to reaction products as shown below.

Load predefined compounds templates to ease set up of a DDI
Itraconazole is a predefined compound
Metabolite Hydroxy-Itraconazole is predefined for Itraconazole
Process type is predefined for Itraconazole/Hydroxy-Itraconazole
Expression levels of enzymes needs to be specified
Processes associated with Itraconazole and Hydroxy-Itraconazole in the pre- defined template
Definition of administration protocols for each compound from available building blocks
Analysis view of all Itraconazole, Hydroxy-Itraconazole and Midazolam
Reaction diagram is the graphical representation of the metabolic network