Target-Mediated Drug Disposition Should Be Interpreted Together with Pharmacological Feedback

Target-mediated drug disposition (TMDD) is commonly interpreted as a pharmacokinetic consequence of saturable binding between a drug and a finite-capacity pharmacological target. That formulation is indispensable but incomplete when treatment changes the biological state that determines subsequent disposition. Target abundance can vary across tissues and individuals, target turnover can create delayed recovery, pharmacological action can deplete or expand accessible target pools, and disease improvement can alter nonspecific clearance mechanisms independently of target binding. Under these conditions, exposure, target state, pharmacodynamic response, and clearance become temporally coupled rather than directionally ordered. This Current Opinion argues that TMDD should therefore be interpreted within a longitudinal pharmacokinetic–pharmacodynamic state framework whenever the determinants of target-mediated clearance are themselves treatment responsive. Classical TMDD concepts remain necessary, but nonlinear pharmacokinetics alone cannot identify the responsible mechanism, plasma linearity does not exclude local target-mediated depletion, and good model fit does not establish mechanistic uniqueness. Evidence from monoclonal antibodies, bispecific constructs, antibody–drug conjugates, soluble-target systems, small molecules, and target-depleting therapies illustrates several distinct routes through which pharmacology can reshape subsequent disposition. A proposed interpretation framework separates measured exposure from latent target state, distinguishes target-mediated feedback from disease-mediated changes in nonspecific clearance, and treats target abundance, turnover, internalization, recycling, and competing nonlinear pathways as context-dependent state variables rather than interchangeable explanations. The clinical implication is not that every TMDD model requires additional feedback compartments, but that reciprocal biology should be considered whenever post-treatment target or disease states plausibly alter future exposure.