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Pharmacokinetic-pharmacodynamic modeling of apratastat: a population-based approach.

Authors
  • Shu, Cathye
  • Zhou, Honghui
  • Afsharvand, Mehri
  • Duan, Larry
  • Zhang, Hui
  • Noveck, Robert
  • Raible, Donald
Type
Published Article
Journal
Journal of clinical pharmacology
Publication Date
Apr 01, 2011
Volume
51
Issue
4
Pages
472–481
Identifiers
DOI: 10.1177/0091270010372389
PMID: 21059888
Source
Medline
License
Unknown

Abstract

Apratastat is an orally active, potent, and reversible dual inhibitor of tumor necrosis factor-α converting enzyme (TACE) and matrix metalloproteinases (MMPs). This study characterizes the pharmacodynamic (PD) effect of apratastat following oral administration on tumor necrosis factor-alpha (TNF-α) release. Data were obtained from 3 clinical studies carried out in healthy subjects. Apratastat was administered orally in these studies as single doses or multiple doses (twice daily). The inhibition of TNF-α release by apratastat was investigated in studies of in vitro, ex vivo, and in vivo. Inhibitory E(max) models were used to characterize the inhibition of TNF-α release in both in vitro and ex vivo studies. Apratastat inhibited TNF-α release with a population mean IC(50) of 144 ng/mL in vitro and of 81.7 ng/mL ex vivo, respectively. The relationship between TNF-α and apratastat plasma concentration in the endotoxin-challenged study in healthy subjects was well characterized by a mechanism-based PD population model with IC(50) of 126 ng/mL. Apratastat can potently inhibit the release of TNF-α in vitro, ex vivo, and in vivo. Even though the dosage provided adequate exposure to inhibit TNF-α release, apratastat was not efficacious in rheumatoid arthritis (RA). This inconsistency between TNF-α inhibition and the clinical response requires further investigation.

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