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


Journal Article

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.

Full Text

Cited Authors

  • Shu, C; Zhou, H; Afsharvand, M; Duan, L; Zhang, H; Noveck, R; Raible, D

Published Date

  • April 2011

Published In

Volume / Issue

  • 51 / 4

Start / End Page

  • 472 - 481

PubMed ID

  • 21059888

Pubmed Central ID

  • 21059888

Electronic International Standard Serial Number (EISSN)

  • 1552-4604

International Standard Serial Number (ISSN)

  • 0091-2700

Digital Object Identifier (DOI)

  • 10.1177/0091270010372389


  • eng