TY - JOUR
T1 - In vivo evaluation of the novel calcineurin inhibitor ISATX247 in Non-Human primates
AU - Stalder, Mario
AU - Bîrsan, Tudor
AU - Hubble, Richard W.
AU - Paniagua, Ricardo T.
AU - Morris, Randall E.
N1 - Funding Information:
Supported by the Ralph and Marian Falk Medical Trust, the HEDCO Foundation and Isotechnika, Inc. (Edmonton, Alberta, Canada). M.S. supported by the Foundation for Research in Cardiac Surgery, University Hospital, Berne, Switzerland. T.B. supported by the Austrian Science Fund (FWF).
PY - 2003/12
Y1 - 2003/12
N2 - 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.
AB - 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.
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U2 - 10.1016/S1053-2498(03)00033-0
DO - 10.1016/S1053-2498(03)00033-0
M3 - Article
C2 - 14672749
AN - SCOPUS:0345735942
SN - 1053-2498
VL - 22
SP - 1343
EP - 1352
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
IS - 12
ER -