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.

ABT‐384 is a potent and selective inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1). The pharmacokinetics of ABT‐384 was evaluated in healthy volunteers in single‐dose (1, 8, 20, 50, 120 and 240 mg) and multiple‐dose studies (1, 2, 4, 8, 20, 30 and 100 mg once daily). Less than dose‐proportional pharmacokinetics of ABT‐384 was observed when ABT‐384 was administered at single doses lower than 8 mg. This nonlinear phenomenon disappeared after repeated doses. The dose‐normalized plasma concentration–time curves superposed across all dose groups on day 7, but not on day 1. This phenomenon cannot be explained by the half‐life of ABT‐384. Based on available data, the nonlinearity is likely due to binding of ABT‐384 to a high‐affinity‐low‐capacity site, such that this interaction was reflected in ABT‐384 pharmacokinetics. To characterize the pharmacokinetics of ABT‐384, a population pharmacokinetic model for ABT‐384 was constructed. The model provided reasonable fitting for both single‐ and multiple‐dose data. Further investigation is warranted to evaluate the disposition of ABT‐384 at low doses using a larger number of subjects. The constructed model would be useful in predicting ABT‐384 concentrations at different doses and guiding the selection of dosing regimens in further clinical trials. Copyright © 2014 John Wiley & Sons, Ltd.