Implementation of an approximate input forcing function for modelling single tissues in the Open Pharmacology Suite

Objectives: The PK-Sim®software is used for the development of whole-body physiologically-based pharmacokinetic (PBPK) models. During model development parameters for drug disposition must be provided, often sourced from in vivo/in vitro experiments. If these parameters are influential, misspecification in a single organ can impact the entire PBPK model. Through development of single-tissue models, initial estimates for influential parameters can be determined in a simpler environment. This study aimed to develop a method using the Open Pharmacology Suite (containing PK-Sim®and MoBi®), which allows for the development of single-tissue models.

Methods: A method was developed in MoBi®that uses models developed in PK-Sim®and converts them into single-tissue models. It uses curve fitting equations as a forcing function, which is then corrected to account for changes caused by step-wise integration during simulation. This method was evaluated to ensure that tissue concentrations of single-tissue models closely represent the whole-body model tissue concentrations that they were based on.

Results: The forcing functions used by the method were found to be accurately implemented, with tissue concentrations of most single-tissue models being representative of those in the whole-body model. Single-tissue models that were not representative of the whole-body model, had a constant proportional error over time. These errors were corrected using a scaling factor on observed concentrations during parameter identification.

Conclusions: The method presented provides a single-tissue development workflow for use with PK-Sim® model development. Once the method has been implemented in model, it can easily be reused in subsequent models to enable the estimation of better initial estimates for whole-body models.