Importance of stability analysis when using non-linear semi-mechanistic models to describe drug-induced haematotoxicity.

Stability analysis, often overlooked in pharmacometrics, is essential to explore dynamical systems. The model developed by Friberg 1 to describe drug-induced haematotoxicity is widely used to support decisions across drug development, and parameter values are often identified from observed blood counts. We use stability analysis to study the parametric dependence of stable and unstable solutions of several Friberg-type models, and highlight the risks associated with system instability in the context of non-linear mixed effects modelling. We emphasize the consequences of unstable solutions on prediction performance by demonstrating non-biological system behaviours in a real case study of drug-induced thrombocytopenia. Ultimately, we provide simple criteria for identifying parameters associated with stable solutions of Friberg-type models. For instance, in the original Friberg model, we find that stability depends only on the parameter which governs the feedback from peripheral cells to progenitors and provide the exact range of values which results in stable solutions.