A computer-aided framework for development, identification and management of physiologically-based pharmacokinetic models

The objective of this work is the development of a generic computer-aided modelling framework to support the development of physiologically-based pharmacokinetic models thereby increasing the efficiency and quality of the modelling process. In particular, the framework systematizes the modelling process by identifying the workflow involved and providing the required methods and tools for model documentation, construction, analysis, identification and discrimination. The application and benefits of the developed framework are demonstrated by a case study related to the whole-body physiologically-based pharmacokinetic modelling of the distribution of the drug cyclosporin A in rats and humans. Four alternative candidate models for rats are derived and discriminated based on experimental data. The model candidate that is best represented by the experimental data is scaled-up to a human being applying physiologically-based scaling laws and identifying model parameters that can be re-fitted by the limited experimental data accessible for humans using sensitivity and identifiability analysis techniques.