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Pharmacokinetic‐Pharmacodynamic Modeling of Apratastat: A Population‐Based Approach
Author(s) -
Shu Cathye,
Zhou Honghui,
Afsharvand Mehri,
Duan Larry,
Zhang Hui,
Noveck Robert,
Raible Donald
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010372389
Subject(s) - ex vivo , pharmacology , in vivo , tumor necrosis factor alpha , pharmacodynamics , pharmacokinetics , medicine , population , rheumatoid arthritis , ic50 , in vitro , chemistry , immunology , biology , biochemistry , microbiology and biotechnology , environmental health
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.