A Pharmacometric Workflow for Resolving Model Instability in Model Use-Reuse Settings.

The development of fit-for-purpose pharmacokinetic-pharmacodynamic (PKPD) models based on clinical and pre-clinical data is a critically important process in model informed drug development. This process is often hampered by modeling stability issues that are often multifactorial in nature and difficult to overcome, leading to protracted model building and arbitrary simplification of the model. This tutorial provides a heuristic workflow to help identify and resolve issues relating to model instability. The approach is centered on analyses undertaken using NONMEM, but the concepts can be generalized to other software used for population analysis of pharmacokinetics (PK) or PKPD data.