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 and increased lymphocytes in lymph nodes and Peyer's patches. Here, we investigated 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 parameters, lymphocyte phenotype (CD3, CD4, CD8, CD20), cell apoptosis, ex vivo blood cell proliferation in response to mitogens and drug blood levels were monitored during treatment and up to 4 weeks thereafter.


RESULTS
FTY720 administered p.o. in baboons at 0.3 mg/kg/day caused a marked decrease in circulating lymphocytes within 4 h of treatment, reaching 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. CD4+ cells were slightly more affected than CD8+ cells. The response onset was faster and the duration longer at higher dose, but the maximal peripheral lymphodepletion achieved was similar within the dose range 0.03-0.3 mg/kg tested. Ex vivo mitogen-induced lymphoproliferation was drastically decreased after FTY720 treatment, corresponding to the reduced blood lymphocyte counts. The blood drug levels measured after FTY720 administration correlated well with the dose applied but there was a poor correlation between FTY720 blood levels and the extent of peripheral lymphodepletion, suggestive of a high tissue distribution of the drug. When compared with cynomolgus monkeys 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/kg. However, the stabilized drug blood levels and peripheral lymphodepletion achieved after 7 days of FTY720 0.03 mg/kg/day were similar in both nonhuman primate species.


CONCLUSIONS
FTY720 was well tolerated and was effective in terms of peripheral T- and B lymphodepletion in baboons, indicating that it could be used in protocols of allo- and xenotransplantation. The pharmacokinetic and pharmacodynamic profiles of FTY720 in baboons suggest the use of high induction doses to optimize immediate response followed by a reduced dose regimen for drug maintenance.
Quesniaux
V
V
Novartis Pharma Transplantation Research, Basel, Switzerland. valerie.quesniaux@pharma.Novartis.com
Fullard
L
L
Arendse
H
H
Davison
G
G
Markgraaff
N
N
Auer
R
R
Ehrhart
F
F
Kraus
G
G
Schuurman
H J
HJ
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods*; D008252:Macaca fascicularis; D010215:Papio; D011409:Propylene Glycols / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013045:Species Specificity; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine