Journal article
General Pharmacokinetic Features of Small-Molecule Compounds Exhibiting Target-Mediated Drug Disposition (TMDD): A Simulation-Based Study
Journal of clinical pharmacology, Vol.59(3), pp.394-405
03/01/2019
DOI: 10.1002/jcph.1335
PMID: 30387863
Abstract
Although target-mediated drug disposition (TMDD) can occur in both large- and small-molecule compounds, TMDD in small-molecule compounds has received much less attention due to its lower prevalence. To facilitate the identification of nonlinear pharmacokinetics of small-molecule compounds caused by TMDD, a comprehensive simulation was conducted in the current study to provide the general pharmacokinetic features of small-molecule compounds exhibiting TMDD. Various conditions, including single escalating intravenous bolus doses, multiple escalating intravenous bolus doses, and intravenous infusion, were simulated for small-molecule compounds with saturable binding to (1) targets located in tissues and (2) targets located in plasma. Sobol global sensitivity analysis was performed to evaluate the impact of key parameters (R-max, k(on) and k(off)) in a small-molecule TMDD model on the apparent volume of distribution and apparent clearance. Our simulation data indicated that small-molecule compounds with saturable binding to targets in plasma demonstrate distinctly different TMDD behavior compared with those with binding to targets in tissue. Sobol global sensitivity analysis results showed that, in general, k(off) is much more influential than k(on) and R-max on apparent clearance and apparent volume of distribution. The TMDD features predicted in various situations in the current work could serve as a valuable reference to help quickly recognize TMDD when it does happen in a small-molecule compound. The TMDD principals summarized based on our simulation could be used to aid pharmacokinetic data interpretation, dose regimen optimization, and clinical trial design of small-molecule drugs exhibiting TMDD.
Details
- Title: Subtitle
- General Pharmacokinetic Features of Small-Molecule Compounds Exhibiting Target-Mediated Drug Disposition (TMDD): A Simulation-Based Study
- Creators
- Thanh Bach - University of IowaYu Jiang - University of IowaXiaoyan Zhang - Adc TherapeuticsGuohua An - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of clinical pharmacology, Vol.59(3), pp.394-405
- Publisher
- Wiley
- DOI
- 10.1002/jcph.1335
- PMID
- 30387863
- ISSN
- 0091-2700
- eISSN
- 1552-4604
- Number of pages
- 12
- Language
- English
- Date published
- 03/01/2019
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984365889502771
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