Validity conditions of approximations for a target-mediated drug disposition model: A novel first-order approximation and its comparison to other approximations

Target-mediated drug disposition (TMDD) is a phenomenon characterized by a drug’s high-affinity binding to a target molecule, which significantly influences its pharmacokinetic profile within an organism. The comprehensive TMDD model delineates this interaction, yet it may become overly complex and computationally demanding in the absence of specific concentration data for the target or its complexes. Consequently, simplified TMDD models employing quasi-steady state approximations (QSSAs) have been introduced; however, the precise conditions under which these models yield accurate results require further elucidation. Here, we establish the validity of three simplified TMDD models: the Michaelis-Menten model reduced with the standard QSSA (mTMDD), the QSS model reduced with the total QSSA (qTMDD), and a first-order approximation of the total QSSA (pTMDD). Specifically, we find that mTMDD is applicable only when initial drug concentrations substantially exceed total target concentrations, while qTMDD can be used for all drug concentrations. Notably, pTMDD offers a simpler and faster alternative to qTMDD, with broader applicability than mTMDD. These findings are confirmed with antibody-drug conjugate real-world data. Our findings provide a framework for selecting appropriate simplified TMDD models while ensuring accuracy, potentially enhancing drug development and facilitating safer, more personalized treatments.Author summary: Target-mediated drug disposition (TMDD) is a phenomenon characterized by the high-affinity binding of a drug to its target molecule. The TMDD model can describe the process to elucidate the binding of the drug to its target and its elimination from the body. However, when target or complex concentrations are not available, simpler models of the TMDD model need to be used to avoid over-parameterization and to improve computational efficiency and analysis. Several simplified TMDD models based on quasi-equilibrium, Michaelis-Menten (MM), or quasi-steady-state (QSS) approximation have been proposed. However, their validity conditions have not been fully investigated. In this study, we derive the validity conditions for the approximations of the TMDD model, providing insights into the appropriate use of simplified models. We also propose a first-order approximation of the QSS model, which is faster than the QSS model and more accurate than the MM model. We also applied the simplified models to antibody-drug conjugate real-world data and obtained the same results. Our work provides clear guidance on the use of the simplified TMDD models, potentially leading to improved drug development and safer, more tailored treatments for patients.