Fig. 4.

Workflow to decide between establishing confidence in the application of PBPK model or situations in which simpler models for an intended purpose may be considered. Start with identifying the key PK mechanisms that are relevant for the intended purpose of the application. Next, build the model, ensuring that parameters needed for these mechanisms, especially the sensitive parameters, are estimated from clinical PK data. Verify the model and refine the parameters if necessary. If minimum requirements to establish confidence in the model are not met, simpler models should be preferred. Establishing confidence in sensitive PBPK model parameters for the mechanisms that are identified to be relevant to the intended purpose of a PBPK model application and verifying the model are necessary prior to model application. Hypothesis generation/testing can help resolve parameter non-identifiability through deconvolution of underlying mechanisms, and allows for robust parameterization. PBPK physiologically based pharmacokinetics, PK pharmacokinetics