The novel immunosuppressant FTY720 induces peripheral lymphodepletion of both T- and B-cells in cynomolgus monkeys when given alone, with Cyclosporine Neoral or with RAD.
OBJECTIVE
FTY720 is a new immunosuppressant active in transplantation models, which modulates lymphocyte recirculation, leading to transient peripheral 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 immunosuppressants, Cyclosporin Neoral or RAD, as an introductory study to transplantation protocols.


METHODS
Each of the three phases of the study comprised a 3-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 given as single compound during the first week and in combination with Neoral at 20 mg/kg/day p.o. or RAD at 0.5 mg/kg/day p.o. during the subsequent 2 weeks.


RESULTS
These treatment regimen were well tolerated, except for some body weight loss at high FTY720 dose (0.3 mg/kg/day). FTY720 treatment 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 up to 80-90% was seen with FTY720 doses of 0.1 and 0.3 mg/kg/day. FTY720 blood levels, both trough levels and AUC(0-24 h), showed a linear relationship with FTY720 dose. The reduction in lymphocyte counts was not directly proportional to FTY720 blood levels. The exposure to FTY720 significantly increased upon coadministration of Neoral. This pharmacokinetic interaction was not observed for coadministration of RAD. However, the peripheral lymphodepletion was slightly increased after coadministration of RAD but not of Neoral. This may be related to the intrinsic effects of RAD on hematopoietic cells.


CONCLUSIONS
FTY720 given orally was effective in terms of peripheral T- and B-lymphodepletion and was well tolerated in cynomolgus monkeys even in combination with Cyclosporine Neoral or RAD, indicating that such 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.
Quesniaux
V F
VF
Transplantation Research Department, Novartis Pharma, Basel, Switzerland. quesniaux@cnrs-orleans.fr
Menninger
K
K
Kunkler
A
A
Vedrine
C
C
Bernhard
M
M
Hedinger
R
R
Kraus
G
G
Schuurman
H J
HJ
D000284:Administration, Oral; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D016572:Cyclosporine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods*; D008252:Macaca fascicularis; D011409:Propylene Glycols / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D014181:Transplantation Immunology
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus