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

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.

• Authors: Cathye Shu, Honghui Zhou, Mehri Afsharvand, Larry Duan, Hui Zhang, Robert Noveck, Donald Raible
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 51 Issue 4 Pg. 472-81 (Apr 2011) ISSN: 1552-4604 [Electronic] England
• PMID: 21059888 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, pharmacokinetics, therapeutic use)
• Placebos
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)
• Young Adult