Journal article
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
Journal of clinical pharmacology, Vol.68(5), pp.526-538
05/2023
DOI: 10.1002/jcph.2185
PMID: 36479709
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 11 beta-hydroxysteroid dehydrogenase type 1 (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.
Details
- Title: Subtitle
- 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
- Creators
- Guohua An - University of IowaDavid A. Katz
- Resource Type
- Journal article
- Publication Details
- Journal of clinical pharmacology, Vol.68(5), pp.526-538
- DOI
- 10.1002/jcph.2185
- PMID
- 36479709
- NLM abbreviation
- J Clin Pharmacol
- ISSN
- 0091-2700
- eISSN
- 1552-4604
- Publisher
- Wiley
- Number of pages
- 13
- Language
- English
- Electronic publication date
- 12/28/2022
- Date published
- 05/2023
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; General Internal Medicine; Internal Medicine
- Record Identifier
- 9984365891202771
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