A novel immunosuppressant, FTY720, induces peripheral lymphodepletion of both T- and B cells and immunosuppression in baboons

Objective: FTY720, a new immunosuppressant active in transplantation models , modulates lymphocyte re-circulation, leading to peripheral lymphopenia an d increased lymphocytes in lymph nodes and Peyer's patches. Here, we invest igated the susceptibility of baboons to FTY720 as an introductory study to transplantation protocols. Methods: FTY720 was administered orally to Chacma baboons at 0.3 or 0.1 mg/ kg/day for 3 days or at 0.03 mg/kg/day for 10 days. Haematological paramete rs, lymphocyte phenotype (CD3, CD4, CDS, CD20), cell apoptosis, ex vivo blo od cell proliferation in response to mitogens and drug blood levels were mo nitored during treatment and up to 4 weeks thereafter. Main findings: FTY720 administered p.o. in baboons at 0.3 mg/kg/day caused a marked decrease in circulating lymphocytes within 4 h of treatment, reach ing 60-80% decrease within 24-48 h. The effect of FTY720 was seen both on T - and B cells, although it was slightly more rapid/pronounced on T cells. C D4(+) cells were slightly more affected than CD8(+) cells. The response ons et was faster and the duration longer at higher dose, but the maximal perip heral lymphodepletion achieved was similar within the dose range 0.03-0.3 m g/kg tested. Ex vivo mitogen-induced lymphoproliferation was drastically de creased after FTY720 treatment, corresponding to the reduced blood lymphocy te counts. The blood drug levels measured after FTY720 administration corre lated well with the dose applied but there was a poor correlation between F TY720 blood levels and the extent of peripheral lymphodepletion, suggestive of a high tissue distribution of the drug. When compared with cynomolgus m onkeys treated in the same way, baboons had a lower initial exposure and a slightly lower response 24 h after one or two doses of FTY720 0.03-0.3 mg/k g. However, the stabilized drug blood levels and peripheral lymphodepletion achieved after 7 days of FTY720 0.03 mg/kg/day were similar in both nonhum an primate species. Conclusions: FTY720 was well tolerated and was effective in terms of periph eral T- and B lymphodepletion in baboons, indicating that it could be used in protocols of allo- and xenotransplantation. The pharmacokinetic and phar macodynamic profiles of FTY720 in baboons suggest the use of high induction doses to optimize immediate response followed by a reduced dose regimen fo r drug maintenance.