A rat pharmacokinetic/pharmacodynamic model for assessment of lipopolysaccharide-induced tumor necrosis factor-alpha production.
BACKGROUND
Tumor necrosis factor-alpha (TNFalpha) participates in many inflammatory processes. TNFalpha modulators show beneficial effects for the treatment of many diseases including rheumatoid arthritis. The purpose of this study was to validate a rat pharmacokinetic/pharmacodynamic (PK/PD) model for rapid assessment of drug candidates that intended to interrupt TNFalpha synthesis or release.


METHODS
Rats received intravenous (IV) or oral administrations of test article or dose vehicle, followed by LPS challenge. Plasma levels of test article and TNFalpha were determined. The areas under the concentration-time curves (AUC(drug) and AUC(TNFalpha)) were calculated. The overall percentage of inhibition on TNFalpha release in vivo was calculated by comparing AUC(TNFalpha) of the test article treated group against that for the vehicle control group.


RESULTS
The dosing vehicles tested in this study did not increase plasma TNFalpha level. At IV dose of up to 100 microg/kg, LPS did not alter the pharmacokinetics of the compound tested. Using a selective TNFalpha converting enzyme (TACE) inhibitor as model compound, this PK/PD model demonstrated its ability to correlate plasma test article concentration with its biological activity of lowering the LPS-induced TNFalpha plasma levels in vivo.


CONCLUSIONS
A rat PK/PD model for evaluation of the effect of drug candidates on LPS-induced TNFalpha synthesis and/or release has been investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test articles.
Wang
Qin
Q
Department of Discovery Pharmacokinetics, Wyeth Research, 1 Burtt Road, Andover, MA 01810, USA. qwang@wyeth.com <qwang@wyeth.com>
Zhang
Yuhua
Y
Hall
J Perry
JP
Lin
Lih-Ling
LL
Raut
Uma
U
Mollova
Nevena
N
Green
Neal
N
Cuozzo
John
J
Chesley
Shannon
S
Xu
Xin
X
Levin
Jeremy I
JI
Patel
Vikram S
VS
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008954:Models, Biological; D051381:Rats; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C499807:(2R, 3S)-2-(((4-(2-butynyloxy)phenyl)sulfonyl)amino)-N,3-dihydroxybutanamide; D008070:Lipopolysaccharides; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat