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

J Clin Pharmacol. 2011 Apr;51(4):472-81. doi: 10.1177/0091270010372389. Epub 2010 Nov 8.


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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Endotoxins / pharmacology
  • Humans
  • Lipopolysaccharides / pharmacology
  • Male
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / metabolism
  • Middle Aged
  • Models, Biological
  • Morpholines / administration & dosage*
  • Morpholines / pharmacokinetics*
  • Morpholines / therapeutic use
  • Placebos
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult


  • Endotoxins
  • Lipopolysaccharides
  • Matrix Metalloproteinase Inhibitors
  • Morpholines
  • Placebos
  • Tumor Necrosis Factor-alpha
  • apratastat
  • Matrix Metalloproteinases