Target-mediated drug disposition and dynamics

Nonlinear pharmacokinetics and pharmacodynamics may result from several capacity-limited processes and often represent complicating factors in characterizing the pharmacological properties of drugs. Target-mediated drug disposition (TMDD) corresponds to a special case wherein a significant proportion of a drug (relative to dose) is bound with high affinity to a pharmacological target, such that this interaction is reflected in the pharmacokinetic properties of the drug. Dose-dependent effects on apparent pharmacokinetic parameters may manifest, including the steady-state volume of distribution and total systemic clearance. Although a few small molecular weight compounds have been identified to exhibit TMDD, the incidence of TMDD is likely to increase particularly among emerging biotechnology pharmaceuticals. The goal of this commentary is to describe the basic tenets of TMDD and discuss several mathematical modeling approaches for characterizing this phenomenon. Whereas traditional pharmacokinetic/pharmacodynamic models assume that the amount of the drug–target complex is negligible relative to the total amount of drug in the body, integrated mechanism-based models of TMDD incorporate the binding and stoichiometry of drug–target binding. These models may be utilized to infer the time-course of inaccessible system variables, such as the in vivo density of the drug–target complex, and provide a suitable platform for ascertaining the apparent pharmacodynamic implications of TMDD.