PK-Sim 5 - From Individual to Population
PK-Sim® is a comprehensive software tool for whole-body physiologically based pharmacokinetic modeling. It allows rapid access to all relevant anatomical and physiological parameters for humans and the most common laboratory animals (mouse, rat, minipig, dog, and monkey) that are contained in the integrated database. Further, it provides access to different PBPK calculation methods to allow fast and efficient model building and parameterization.
PK-Sim® automatically considers relevant generic passive processes (e.g. distribution through the blood flow), and specific active processes (e.g. metabolization by a certain enzyme) can be specified as needed. Like most PBPK modeling tools, PK-Sim® is designed for use by non-modeling experts and only allows 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.
Full integration and compatibility with MoBi®
More importantly, PK-Sim® is fully compatible with the expert modeling software tool MoBi® thereby allowing full access to all model details including the option for extensive model modifications and extensions. This allows the establishment of customized systems pharmacology models to deal with the challenges of modern drug research and development.
More versatility and flexibility with building blocks
PK-Sim® uses building blocks that are grouped into Individuals, Populations, Compounds, Formulations, Administration Protocols, Events, and Observed Data. The different building blocks are described in detail here: Building Blocks in PK-Sim® and MoBi®.
Once the required building blocks have been set up, they are combined to create a model. One obvious advantage of using building blocks lies in the fact that they can be reused. For example, after having established a model for a drug after single dose intravenous administration to an animal species, the user can go and substitute the individual by a suitably parameterized virtual human population and obtain a first in man simulation model. This model can than be modified further by e.g. substituting the formulation for examining a controlled-release per-oral dosing schedule or by substituting the administration protocol to simulate the effects of multiple dosing. An obvious substitute the compound to obtain a simulation model for a different drug in an identical population under identical conditions.
Target concentration accuracy: PK-Sim Express®
An additional cornerstone of the new PK-Sim® has been set with the integration of PK-Sim® Express - a gene expression database that facilitates analyses of ADME processes in the target tissue of interest by accounting for protein expression levels in the tissue of interest. The resulting model presents a more accurate physiological description of the molecular mechanisms underlying metabolism and distribution.
New compartmental gastro-intestinal transit model
With the aim of providing a tool for predicting absorption of orally administered drugs more precisely - including drug-drug interactions within the gut wall and the effects of active transport and gut wall metabolism - the existing absorption model of PK-Sim® was revised. This revised model reflects more detailed knowledge of human gastrointestinal physiology including fluid secretion and absorption and comprises an elaborate representation of the intestinal mucosa.
With this detailed representation of the mucosa, the model is optimally equipped to support the development of mechanistic models of active transport processes and gut wall metabolism.
Full transparency and improved user convenience: History and Rollback function
In both PK-Sim and MoBi, all user actions performed within a project are sequentially listed and stored. All previous project states can be reinstated at any time. Rollback to a previous state is not an undo function but rather a new action that is sequentially stored in the history. It also provides a full documentation of the model building process. This feature ensures traceability of all user actions. With the goal of being fully transparent in regards to parameters and functions used within PK-Sim® and MoBi®, all of them have been made visible. This makes the Computational Systems Biology Software suite a “white box” in its entirety, thereby providing full transparency as demanded by regulatory authorities.