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.