Modules, Philosophy, and Building Blocks
Introduction
The Open Systems Pharmacology Suite (OSPS) contains different software tools and has been designed using a modular concept to allow efficient multi-scale modeling and simulation workflows. The ecosystem of the different software tools and their interactions is explained in the Software Ecosystem section. The central software tools PK-Sim® and MoBi® make use of the building blocks concept as introduced in PK-Sim® and its building blocks and MoBi® and its building blocks.
PK-Sim® is based on a whole-body physiologically-based modeling concept, while the focus of MoBi® lies on modeling complex signaling pathways and extending the standard PBPK framework. The different physiological scales that are covered by the different tools are illustrated below.
PK-Sim®
PK-Sim® is a comprehensive software tool for whole-body physiologically based pharmacokinetic (PBPK) modeling [92]. It enables rapid access to all relevant anatomical and physiological parameters for humans and common laboratory animals (mouse, rat, minipig, dog, monkey, and rabbit) contained in the integrated database. Users can access different PBPK calculation methods for fast and efficient model building and parameterization. Relevant generic passive processes, such as distribution through blood flows as well as specific active processes, such as metabolization by a particular enzyme, are automatically taken into account by PK-Sim®. Like most PBPK modeling tools, PK-Sim® is designed for use by non-modeling experts and only allows for minor structural model modifications. Unlike most PBPK modeling tools, though, PK-Sim® offers different model structures to choose from, e.g., to account for important differences between small and large molecules (see Model settings). More importantly, PK-Sim® is accompanied by the expert modeling software tool MoBi®, allowing full access and transparency to all model details, including the option for extensive model modifications and extensions. This way, customized systems pharmacology models may be set up to deal with the challenges of modern drug research and development.
PK-Sim® applies the building blocks concept, separating information used for model building into groups: Individuals, Populations, Compounds, Formulations, Administration Protocols, Events, Observers, and Observed Data. The different building blocks are described in detail in “Working with PK-Sim®”. Building blocks from these groups are combined to generate a model. The advantage of building blocks is that they can be reused and combined to create different models. For example, after establishing a drug model after single-dose intravenous administration to an animal species, substitute the individual with a suitably parameterized virtual human population and obtain a first-in-man simulation model. Further substitute the formulation to get a controlled-release per oral simulation model, substitute the protocol to obtain a multiple dose simulation model, or replace the compound to obtain a simulation model for another drug.
PK-Sim® will be described in detail in Working with PK-Sim®.
MoBi®
MoBi® is a systems biology software tool for multiscale physiological modeling and simulation. Within the restrictions of ordinary differential equations, almost any kind of (biological) model can be imported or set up from scratch. Examples include biochemical reaction networks, compartmental disease progression models, or PBPK models. However, de novo development of a PBPK model, for example, is very cumbersome, such that the preferred procedure is to import them from PK-Sim®. Importantly, MoBi® also allows for the combination of the described examples and thereby is a very powerful tool for modeling and simulation of multi-scale physiological systems covering molecular details and whole-body architecture.
De novo model establishment and simulation are supported by graphical tools and building blocks to support expert users. MoBi® uses building blocks that are grouped into Molecules, Reactions, Spatial Structures, Passive Transports, Observers, Events, Molecule Start Values, Parameter Start Values, and Observed Data. The different building blocks are described in detail in Working with MoBi®. Building blocks out of the above-mentioned groups can be combined to generate models. The advantage of building blocks is that they can be reused. Examples:
a different set of starting values may define a new scenario, situation, or individual.
refine a Reaction(s) network and update it in all tissues where it should be considered.
All building blocks are further organized into modules. The modules are either full-scale PBPK models imported from PK-Sim, or extensions to the default PBPK structure, effect models, or any model customization. The modules are combined into simulations, allowing for flexible and efficient model development and simulation.
MoBi® will be described in detail in Working with MoBi®.
Software Ecosystem
The software ecosystem is outlined in the figure below.
Apart from the two central, graphical user interface (GUI)- based software tools PK-Sim® and MoBi®, the software platform is supported by an ecosystem of various R packages, including a qualification framework, validation and automation tools, and specialized workflows for modeling and simulation.
Qualification framework
The qualification framework enables automated validation of various scenarios (use cases) supported by the OSP platform. This technical framework is used, for example, to release a new version of the OSP Suite in full confidence by automatically verifying that an ever-growing list of scenarios is performing as expected. The qualification framework will be described in detail in Qualification.
Validation and automation tools
Validation and automation tools include, for example:
Installation Validator: enables "1-Click" validation of the OSP Suite installation on a target computer. The validation is performed by execution of the predefined set of simulation scenarios and comparison of the simulated results with the (validated) reference values.
Command Line Interface (CLI): allows batch processing of multiple projects in PK-Sim and is described in Command Line Interface - CLI.
R-packages
The OSP software suite provides a set of packages for the R computing environment that allow scripted workflows with the models developed in PK-Sim® and MoBi®.
ospsuite package provides the functionality of loading, manipulating, and simulating the simulations created in PK-Sim® and MoBi®. It also offers extended workflows such as parameter sensitivity or PK-parameter calculation. The package is described in detail in R documentation.
tlf package offers a set of functions and methods for creating standardized reporting Tables, Listings, and Figures.
ospsuite.reportingengine for automated generating of model reports.
ospsuite.parameteridentification provides the functionality of performing parameter identification (i.e., fitting the model to observed data) with simulations. The package is currently under development and everyone is encouraged to contribute.
OSP Model exchange format
Models created in PK-Sim® or MoBi® can be exported in PK Modeling Language (*.pkml) format and shared between the OSP tools. Internally, the PKML file format is an XML format with a predefined structure.
Import and Export
Apart from the communication and exchange via R, PK-Sim® and MoBi® have import and export functions for MS Excel®, CSV, and NONMEM® that allow for the import of experimental data or the export of simulation results, for example. MoBi® has SBML import functionalities.
PK-Sim can also import and export project snapshots in JSON format (s. Exporting Project to Snapshot for details).
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