The novel immunosuppressant FTY720 induces peripheral lymphodepletion of both T- and B-cells in cynomolgus monkeys when given alone, with Cyclosporine Neoral (R) or with RAD

Objective: FTY720 is a new immunosuppressant active in transplantation mode ls, which modulates lymphocyte recirculation, leading to transient peripher al lymphopenia and increased lymphocytes in lymph nodes and Peyer's patches . Here, we investigated the susceptibility of cynomolgus monkeys to FTY720 given orally either alone or in combination with two other immunosuppressan ts, Cyclosporin Neoral(R) or RAD, as an introductory study to transplantati on protocols. Methods: Each of the three phases of the study comprised a S- week treatment period with FTY720 administered daily orally at 0.3, 0.1 or 0.03 mg/kg/day, respectively, followed by a 3-week recovery. FTY720 was giv en as single compound during the first week and in combination with Neoral( R) at 20 mg/kg/day p.o. or RAD at 0.5 mg/kg/day p.o. during the subsequent 2 weeks. Main findings: These treatment regimen were well tolerated, except for some body weight loss at high FTY720 dose (0.5 mg/kg/day). FTY720 trea tment resulted in a rapid decrease of white blood cell counts which reached a plateau after 3 days. A decrease in both T- and B-lymphocyte counts by u p to 80-90% was seen with FTY720 doses of 0.1 and 0.3 mg/kg/day. FTY720 blo od levels, both trough levels and AUC(0-24 h), showed a linear relationship with FTY720 dose. The reduction in lymphocyte counts was not directly prop ortional to FTY720 blood levels. The exposure to FTY720 significantly incre ased upon coadministration of Neoral(R). This pharmacokinetic interaction w as not observed for coadministration of RAD. However, the peripheral lympho depletion was slightly increased after coadministration of RAD but not of N eoral(R). This may be related to the intrinsic effects of RAD on hematopoie tic cells. Conclusions: FTY720 given orally was effective in terms of perip heral T- and B-lymphodepletion and was well tolerated in cynomolgus monkeys even in combination with Cyclosporine Neoral(R) or RAD, indicating that su ch combination protocols could be used in allo- and xenotransplantation in this species. However, the data indicate a potentiation of FTY720 exposure by CsA coadministration and additional lymphodepletion by coadministration of FTY720 and RAD which should be carefully monitored. (C) 2000 Elsevier Sc ience B.V. All rights reserved.