Concept of Pharmacologic Target-Mediated Drug Disposition in Large-Molecule and Small-Molecule Compounds

J Clin Pharmacol. 2020 Feb;60(2):149-163. doi: 10.1002/jcph.1545. Epub 2019 Dec 2.


Target-mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetic (PK) phenomenon that is caused by high-affinity binding of a compound to its pharmacologic targets. As the interaction between a drug and its pharmacologic target belongs to the process of pharmacodynamics (PD), TMDD can be viewed as a consequence of "PD affecting PK." Although there are numerous TMDD-related articles in the literature, most of them focus on characterizing TMDD using various mathematical models, which may not be suitable for those readers who have little interest in mathematical modeling and only want to have an understanding of the basic concept. The goal of this review is to serve as a "primer" on TMDD. This review explains (1) how TMDD happens; (2) why large-molecule and small-molecule compounds exhibiting TMDD demonstrate substantially different nonlinear PK behaviors; (3) what nonlinear PK profiles look like in large-molecule and small-molecule compounds exhibiting TMDD, using pegfilgrastim, erythropoietin, ABT-384, and linagliptin as case examples; and (4) how to identify whether the nonlinear PK of a compound is because of TMDD.

Keywords: ABT-384; Target-mediated drug disposition; erythropoietin; linagliptin; nonlinear PK; pegfilgrastim.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Delivery Systems
  • Humans
  • Nonlinear Dynamics
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics*
  • Tissue Distribution


  • Pharmaceutical Preparations