Preliminary in vivo pharmacokinetic and pharmacodynamic evaluation of a novel calcineurin-independent inhibitor of NFAT.
A-285222 (A-285) is a bis-trifluoromethyl-pyrazole (BTP), a novel class of immunosuppressive agents that inhibit NFAT activity in vitro in human and non-human primate cells through a calcineurin-independent mechanism. In this preliminary study, we treated cynomolgus monkeys with different doses of A-285 for several days. Blood was collected from all animals at different times during the study. From these samples, plasma concentrations of A-285 were measured by liquid chromatography/mass spectrometry (LC/MS), and intracellular T-cell production of the cytokines IL-2, IFN-gamma, and TNF-alpha was quantified by flow cytometry using a mitogen-stimulated whole blood assay. Marked inhibition of cytokine production occurred after administration of the first dose of A-285, and this effect was comparable to that of cyclosporine. While neurological toxic side effects were seen when the plasma concentration of A-285 exceeded 4 microg/ml, at lower plasma levels the drug was well tolerated over 2 weeks and its pharmacodynamic effects were sustained throughout this time.
Bîrsan
Tudor
T
Department of Cardiothoracic Surgery, Transplantation Immunology Laboratory, Stanford, California, USA.
Dambrin
Camille
C
Marsh
Kennan C
KC
Jacobsen
Wolfgang
W
Djuric
Stevan W
SW
Mollison
Karl W
KW
Christians
Uwe
U
Carter
George W
GW
Morris
Randall E
RE
D000284:Administration, Oral; D000818:Animals; D019703:Calcineurin / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D008252:Macaca fascicularis; D008297:Male; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014157:Transcription Factors; D014297:Trimethylsilyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
C494244:A 285222; D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011720:Pyrazoles; D014157:Transcription Factors; D014297:Trimethylsilyl Compounds; D019703:Calcineurin