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

Authors

Yu Fu, Liang Yang, Hong Su, Ye Yao, Yu Li, Peiming Ma

Published in

The AAPS journal. Volume 28. Issue 4. Jul 07, 2026. Epub Jul 07, 2026.

Abstract

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.

PMID:
42484754
Bibliographic data and abstract were imported from PubMed on 22 Jul 2026.

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