Calculating Receptor Occupancy using TMDD Models - What has to be Considered?

Target-mediated drug disposition (TMDD) models are often used to describe drug-receptor interactions and help derive receptor occupancy (RO), i.e., the ratio of drug-receptor complex to total receptors, which is important for understanding drug responses especially in early clinical development. A full TMDD model can be complex, and data may not always be sufficient for fitting the model. In such cases, approximations of the full TMDD model (e.g., Michaelis-Menten, rapid-binding or quasi-steady-state models) are used, and RO is calculated often using the Michaelis-Menten constant ( ${\text{K}}_{\text{M}}$ ) derived from these models. In this simulation study, we conduct analyses using models with parameter values sourced from literature to show that RO derived from ${\text{K}}_{\text{M}}$ may not reflect the true RO. When data available for model-fitting consists only of drug concentrations, the accuracy and precision of the model parameters such as ${\text{K}}_{\text{M}}$ depend on the selected approximate models and their model assumptions, e.g., where binding takes place. We hope these analyses provide insights in performing model-derived RO predictions and dose optimization-which often depends on RO-in clinical drug development.