Importance of Target-Mediated Drug Disposition (TMDD) of Small-Molecule Compounds and Its Impact on Drug Development-Example of the Class Effect of HSD-1 Inhibitors.

Abstract

With more potent drug candidates being developed, the incidence of target-mediated drug disposition (TMDD) in small-molecule compounds has significantly increased in the past decade. Moreover, TMDD appears to apply to some small-molecule compound classes. The main purpose of the current review is to increase the awareness of TMDD in a series of small-molecule inhibitors of 11β-hydroxysteroid dehydrogenase type1 (HSD-1) using ABT-384, SPI-62, MK-0916, BMS-823778, and BI-187004 as case examples. Although developed independently by different pharmaceutical companies, these HSD-1 inhibitors demonstrated strikingly similar nonlinear pharmacokinetic behaviors when wide dose ranges were evaluated in first-in-human (FIH) single ascending dose (SAD) and multiple ascending dose (MAD) studies. Recognizing TMDD in small-molecule compounds is important, as the information can be leveraged to select the appropriate dose regimen, improve clinical trial design, as well as predict pharmacological target occupancy. In this review, we summarize the general pharmacokinetic features that facilitate the recognition of small-molecule TMDD, provide case examples of specific HSD-1 inhibitors, highlight the importance of recognizing TMDD of small-molecule compounds during clinical development, and comment on the importance of utilizing pharmacometric modeling to facilitate the quantitative understanding of small-molecule compounds exhibiting TMDD.