To leverage the mechanistic strengths of PBPK models, it is essential to establish confidence in the mechanisms that are relevant to an application.

Establishing confidence in PBPK models is challenged by poor in vitro-in vivo correlations, knowledge gaps in system parameters and in mechanisms impacting an application, as well as parameter non-identifiability.

Uncertainty analysis and hypothesis testing can be used to overcome some of these challenges.

If the mechanistic basis of a PBPK model cannot be established, then simpler models and/or evidence-based approaches should be considered.