FTY720

Abstract

FTY720 is a new immunosuppressive drug that is effective in a variety of experimental models of allo- and xenotransplantation, chronic rejection, autoimmune diseases, and inhibition of tumor growth. The therapeutic effects of FTY720 are related to its ability to produce peripheral blood lymphopenia without inducing generalized immunosuppression, since granulocytes, monocytes, and T- and B-cell memory responses are unimpaired. Its pharmacodynamic properties appear to be derived from its dose-dependent agonistic effect on sphingosine 1-phosphate receptors present in the membrane of lymphocytes and other cells, leading to a variety of biologic effects from lymphocyte sequestration into secondary lymphoid organs to cell cycle arrest and apoptosis. FTY720 shows a long absorption phase and terminal half-life (∼108 hours) and a large volume of distribution (∼1400 L). Its pharmacokinetics is dose-proportional with low inter- and intraindividual variability. In kidney transplant patients, FTY720, at doses of 2.5 or 5 mg/d, has been shown to be safe and very effective in association with full or reduced cyclosporine exposure, as well as in combination with everolimus in patients at high risk for developing delayed graft function. The unique pharmacokinetic, pharmacodynamics, and therapeutic effects of FTY720 will allow the design of more effective and less toxic immunosuppressive regimens.