Practical Unidentifiability Of Receptor Density In Target Mediated Drug Disposition Models Can Lead To Over-Interpretation Of Drug Concentration Data

For monoclonal antibodies, mathematical models of target mediated drug disposition (TMDD) are often fit to data in order to estimate key physiological parameters of the system. These parameter estimates can then be used to support drug development by assisting with the assessment of whether the target is druggable and what the first in human dose should be. The TMDD model is almost always over-parameterized given the available data, resulting in the practical unidentifiability of some of the model parameters, including the target receptor density. In particular, when only PK data is available, the receptor density is almost always practically unidentifiable. However, because practical identifiability is not regularly assessed, incorrect interpretation of model fits to the data can be made. This issue is illustrated using two case studies from the literature.