Pharmacokinetic-pharmacodynamic modeling of apratastat: a population-based approach.
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.
Pfizer, 500 Arcola Road, Collegeville, PA 19426, USA.
Cathye
C
Shu
Honghui
H
Zhou
Mehri
M
Afsharvand
Larry
L
Duan
Hui
H
Zhang
Robert
R
Noveck
Donald
D
Raible
D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004731:Endotoxins / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D009025:Morpholines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult
D004731:Endotoxins; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha; C484302:apratastat; D020782:Matrix Metalloproteinases