Target-Mediated Drug Disposition (TMDD) Revisited: High Versus Low-Affinity Approximations of the TMDD Model

Abstract

Target-mediated drug disposition (TMDD) is often associated with high-affinity binding to a target resulting in nonlinear pharmacokinetics. For large molecules, such as monoclonal antibodies, this can lead to increased clearance at sub-saturating concentrations. However, for small molecules, target binding can protect the drug from a fast systemic clearance. Here, we show that both types of behaviors can be described by simple expressions arising from a high-affinity approximation of the standard TMDD model. Interestingly, the celebrated Michaelis–Menten (MM) approximation arises in the opposite limit of low affinity and if the systemic drug clearance is sufficiently slow. Our derivation contains a previously missing factor in front of the MM constant that becomes important when target and drug-target complex elimination rates are different. As a measure of target suppression, we also derive simple expressions for the free target to baseline ratio and compare our approximations with data from large and small molecules.