Send to

Choose Destination
J Clin Pharmacol. 2015 Oct;55(10):1079-85. doi: 10.1002/jcph.531. Epub 2015 Jun 16.

Small-molecule compounds exhibiting target-mediated drug disposition - A case example of ABT-384.

Author information

Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA.
Clinical Pharmacology and Pharmacometrics, Research and Development, AbbVie, North Chicago, IL, USA.


Nonlinearities are frequently encountered in pharmacokinetics, and they can occur when 1 or more processes of absorption, distribution, metabolism, and excretion are saturable. One special source of nonlinearity that has been noticed recently is the saturable binding of the drug to a high-affinity-low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Although TMDD can occur in both small-molecule compounds and large-molecule compounds, the latter has received much more attention because of its high prevalence. With the development of more potent small-molecule drugs acting on highly specific targets and the availability of increasingly sensitive analytical techniques, small-molecule compounds exhibiting TMDD have been increasingly reported in the past several years. ABT-384 is a small-molecule drug candidate that exhibited significant nonlinear pharmacokinetics, potentially imparted by TMDD, in a first-in-human clinical trial conducted in healthy volunteers. Compared with published small-molecule compounds exhibiting TMDD, ABT-384 pharmacokinetic characteristics are more consistent with TMDD. To expand current knowledge of TMDD of small-molecule compounds and increase awareness of this interesting and clinically important phenomenon, in this review the general features of small-molecule compounds exhibiting TMDD are highlighted, with ABT-384 provided as an example.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center