Local depletion of large molecule drugs due to target binding in tissue interstitial space

Drug-target binding determines a drug's pharmacodynamics but can also have a profound impact on a drug's pharmacokinetics, known as target-mediated drug disposition (TMDD). TMDD models describe the influence of drug-target binding and target turnover on unbound drug concentrations and are frequently used for biologics and drugs with nonlinear plasma pharmacokinetics. For drug targets expressed in tissues, the effect of TMDD may not be detected when analyzing plasma concentration curves, but it might still affect tissue concentrations and occupancy. This review aimed to investigate the likeliness of such a scenario by reviewing the literature for a typical range of TMDD parameter values and their impact on local drug concentrations and target occupancy in a whole-body PBPK model with TMDD. Our analysis demonstrated that tissue drug concentrations are impacted and significantly depleted in many physiological scenarios. In contrast, the effect on plasma concentrations is much lower, specifically for smaller organs with lower perfusion. Moreover, in scenarios with fast internalization of the drug-target complex, the distribution of large molecules from plasma to tissue interstitial space emerges as a rate-limiting step for the drug-target interaction. These factors may lead to overpredicting local drug concentrations when considering only plasma pharmacokinetics. A sensitivity analysis revealed the high and not always intuitive impact of drug-specific parameters, including the drug molecule hydrodynamic radius, dissociation constant (K_d), drug-target complex internalization rate constant (k_int), and target dissociation rate constant (k_off), on the drug's pharmacokinetics. Our analysis demonstrated that tissue TMDD needs to be considered even if plasma pharmacokinetics are linear.