Human Safety and Pharmacology of Fty 720

585 The novel immunosuppressant FTY 720 prolongs allograft survival with remarkable potency in animal models, its immunosuppressive effect possibly related to an alteration in lymphocyte homing. A preliminary description of the safety, tolerability and pharmacologic activity of FTY 720 in the first human trial follows. Methods. This study utilized a randomized, double-blind, placebo-controlled, time-lagged, two center, ascending single oral dose (0.25 to 3.5 mg), adaptive design. The thirty-two subjects in this study were stable renal transplant patients, ≥12 months post transplant, age 18-65, on therapeutic levels of Neoral®, with serum creatinine ≤3.0. Standard safety studies and lymphocyte counts were performed. Results. There were no serious adverse events in FTY 720 treated subjects. Twenty-nine adverse events occurred, most of which were distributed equally in the treatment groups. Bradycardia was more common in FTY 720 treated subjects. The effect of FTY 720 on mean lymphocyte count (ratio of FTY 720/placebo) at representative doses is shown in the following figure.FigureAll lymphocyte subsets were equally affected by FTY 720, no consistent changes were noted in monocyte or granulocyte counts. Conclusions. FTY 720 was well tolerated in single doses in humans. At doses up to 1.0 mg, FTY 720 resulted in a rapidly reversible decrease in lymphocyte count, the nadir occurring at approximately 6-12 hours post dose. Higher doses of FTY 720 resulted in more sustained and intense lymphopenia. Future clinical trials of FTY 720 are currently planned.