Small-molecule compounds exhibiting target-mediated drug disposition - A case example of ABT-384.
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.
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA.
Guohua
G
An
Clinical Pharmacology and Pharmacometrics, Research and Development, AbbVie, North Chicago, IL, USA.
Wei
W
Liu
Clinical Pharmacology and Pharmacometrics, Research and Development, AbbVie, North Chicago, IL, USA.
Sandeep
S
Dutta
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors; D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D010879:Piperazines / Q000493:pharmacokinetics*; D014018:Tissue Distribution
C584004:N-(5-(aminocarbonyl)tricyclo(3.3.1.13,7)dec-2-yl)-alpha,alpha-dimethyl-4-(5-(trifluoromethyl)-2-pyridinyl)-1-piperazineacetamide; D010879:Piperazines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane