Background: ISATX247 is a novel calcineurin inhibitor that has shown more potency than cyclosporine in vitro. This is the first in vivo study of the effects of ISATX247 on lymphocyte functions in non-human primates. Methods: Groups of cynomolgus monkeys were treated orally twice daily for 7 days, each dose consisting of 25 mg/kg cyclosporine (n = 5), 25 mg/kg ISATX247 (n = 6) or 50 mg/kg ISATX247 (n = 6). Levels of cyclosporine and ISATX247 in whole blood were measured by liquid chromatography/mass spectrometry. After mitogen stimulation, lymphocyte proliferation was assessed by tritium-labeled thymidine incorporation and by flow cytometry (expression of proliferating cell nuclear antigen in cells in S/G2M phase). Flow cytometry was also used to assess production of intracellular cytokines by T cells (interleukin-2, interferon-γ, tumor necrosis factor-α) and expression of T-cell surface activation antigens (CD25, CD71, CD11a, CD95, CD154). Results: Trough (C14hr) and peak (C3hr) drug levels, as well as area under the concentration-time curve, were significantly higher for cyclosporine than ISATX247 (370 ng/ml vs 70 ng/ml, 877 ng/ml vs 303 ng/ml and 6,262 ng · h/ml vs 1,979 ng · h/ml, respectively). On Day 7 at C14hr, lymphocyte proliferation had been suppressed by approximately 50% in all groups compared with proliferation before treatment. Three hours after dosing, lymphocyte proliferation was inhibited significantly more by ISATX247 (approximately 80%, with no differences between the two ISATX247 dose levels) than by cyclosporine (65% inhibition). Similar differences between the immunosuppressive effects of ISATX247 and cyclosporine were found for inhibition of expression of T-cell surface activation antigens. Despite lower ISATX247 exposures compared with cyclosporine, the cyclosporine treatment only rarely suppressed cytokine production more than treatment with ISATX247. Conclusions: In non-human primates, ISA TX247 produces a greater or similar inhibition of lymphocyte proliferation, expression of T-cell activation surface antigens, and cytokine production when compared with cyclosporine, despite ISATX247's lower blood levels and total exposure. We conclude that ISATX247 suppresses diverse T-cell functions more potently than cyclosporine in non-human primates in vivo.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Cardiology and Cardiovascular Medicine