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Preliminary in vivo pharmacokinetic and pharmacodynamic evaluation of a novel calcineurin‐independent inhibitor of NFAT

Abstract A‐285222 (A‐285) is a bistrifluoromethyl‐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‐γ, and TNF‐α 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 μg/ml, at lower plasma levels the drug was well tolerated over 2 weeks and its pharmacodynamic effects were sustained throughout this time.