Prophylaxis of Acute Renal Allograft Rejection Using Fty720 in Combination With Subtherapeutic Doses of Cyclosporine1

Abstract

Addition of FTY720 therapy to a subtherapeutic CsA immunosuppressive regimen delays the rejection of renal allografts in subhuman primates.

A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments

“…We found no difference between the lower and higher dose of FTY720, however. Our observation is consistent with that of Troncoso et a1 [20], who demonstrated that in combination with sub-therapeutic doses of CsA given to achieve serum trough concentrations of 40 to 200 ng/ml, intravenous administration of FTY720 at 0.1 mg/kg per day or 0.3 mg/kg per day yields a similar prolongation of graft survival, 7 1 days versus 63 days, while the combination of 1 mg/kg per day of FTY720 and CsA reduced graft survival to 48 days by over-immunosuppression. Those findings suggest that, as found in single-drug treatment, a minimal dose of FTY720 is sufficient to produce maximum immunosuppression in a combination therapy.…”

“…Trough blood concentrations at a therapeutic dosage of 0.1 mg/kg per day in dogs ranged from 5 to 10 ng/ml. These target trough levels were similar to those with the recommended trough levels, ranging from 1.25 to 5.27 ng/ml in monkeys [20] and from 0.97 to 8.76 ng/ml in humans [27]. There were no drug interactions between FTY720 and CsA or FK in this study.…”

“…This effect is thought to be caused by enhanced lymphocyte homing, at concentration orders of nanomoles per liter [l, 2, 3,4], via augmented expression of adhesion molecules, Gprotein-coupled chemokine receptors, and their ligands on the lymphocytes and/or high endothelial venules (HEVs) of lymph nodes (LNs) and Peyer's patches (PPs) [5,6,7,81. When FTY720 is administered at higher concentrations [i.e., at more than 2 or 4 pmol/l (700 or 1,400 ngiml)], T cells from MRL/lpr mice, rat spleen cells, human peripheral blood cells, and/or other cell lines, including cancer cells, undergo apoptosis [3, 9, 10, 11, 12, 13, 141. In experimental allogenic organ transplantation studies, FTY720 exhibited mild immunosuppression as a single-drug treatment and, when combined with conventional drugs, had synergistic immunomodulatory activity with or without adverse events [9,15,16,17,18,19,20,21,22,23,24,251. In recent phase I1 trials in denovo renal transplant recipients, FTY 720 appeared effective in the prevention of acute rejection when given with cyclosporine (CsA) and steroids.…”

FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations

“…FTY720 is a novel, high potency immune modulating agent that is remarkably effective in a variety of autoimmune and transplant models [2][3][4][5][6][7] and has recently proved to be effective in renal transplantation in man. [8][9][10] The mechanism of action of FTY720 appears to be distinct from that of any other drug approved or being developed for use in organ transplantation.…”

“…1 It has a remarkable potency in inhibiting rejection of allografts in various experimental animal models [2][3][4][5][6][7] and has recently proved to be safe and effective in renal transplantation in man. [8][9][10] The protective effect correlates with a sequestration of lymphocytes from the peripheral circulation to lymph nodes and Peyer's patches, leading to a reduced infiltration into inflammatory sites and grafted organs.…”