STRUCTURAL IDENTIFIABILITY OF PBPK MODELS - PRACTICAL CONSEQUENCES FOR MODELING STRATEGIES AND STUDY DESIGNS

Physiologically based pharmacokinetic (PBPK) models usually contain un known parameters that need to be estimated by calibration to concentra tion-time profiles from in vivo experiments. However, even with error- free data, the number of parameters that can be estimated in this way is limited, depending on the particular situation. This paper introduc es the concept of structural identifiability of a model, a requirement to make the estimation of parameters by calibration a meaningful unde rtaking. We briefly discuss the techniques - available from systems an alysis - for examining the identifiability of models. Two conditions o f uniqueness are involved, one relating to the model's equations and i ts parameters, the other to the number of available observations in ti me. The assessment of the first uniqueness condition involves rather t edious matrix algebra, requiring the appropriate mathematical expertis e. We therefore give some general results for a particular class of PB PK models, indicating in what situations the first uniqueness conditio n either holds or does not. The assessment of the second uniqueness co ndition does not require specialized skills, and the minimum number of observations in time necessary can be easily determined for any parti cular situation. The practical implications for both modeling strategi es and experimental protocols are discussed.