Preclinical evaluation of a new immunosuppressive agent, FTY720

Troncoso, P.; Kahan, Barry D.

doi:10.1016/s0009-9120(98)00043-5

Cited by 25 publications

(24 citation statements)

References 12 publications

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“…As reported, FTY720-P cross-reacts with all three species. 13 We found that for all compounds tested, their species cross-reactivity was consistent with the human selectivity profile.…”

Section: Resultssupporting

confidence: 53%

No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation

et al. 2014

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Sphingosine-1-phosphate (S1P) is a bioactive metabolite with pleiotropic effects on multiple cellular processes in health and disease. Responses elicited by S1P are a result of binding to five specific G-protein-coupled receptors. We have developed multiple assays to systematically study the downstream signaling of these receptors, including early events such as direct receptor activation (GTPγS) as well as more distal events such as S1P 1 receptor degradation. Employing such assays, we have characterized and compared multiple S1P 1 agonists that are in clinical development including FTY720, BAF312, CS-0777, and other molecules from the S1P 1 patent literature. Our parallel assessment has allowed us to compare their potency against S1P 1 , their selectivity against the four other S1P receptors, as well as species cross-reactivity. We note that all of the compounds studied signal in an identical manner through S1P 1 , leading to receptor degradation.

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“…As reported, FTY720-P cross-reacts with all three species. 13 We found that for all compounds tested, their species cross-reactivity was consistent with the human selectivity profile.…”

Section: Resultssupporting

confidence: 53%

No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation

et al. 2014

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“…FTY720 prolonged canine kidney allograft survival at a dose of 10 mg/ kg [8]. FTY720 also prolonged monkey kidney transplant survival at a dose of 0.3 mg/kg, and it showed no toxic effects [9]. In the rat system, FTY720 has been reported to have beneficial effects on the survival of various other kinds of organ allografts.…”

Section: Discussionmentioning

confidence: 89%

“…It has been reported that FTY720 markedly decreased T cell infiltration into the allografts because of accelerated lymphocyte homing to the lymph nodes and Peyer's patches [9,13], but that this drug did not affect the production of Th1 cell-associated cytokines, especially IL-2, by alloantigen stimulation in rats [4].…”

Section: Discussionmentioning

confidence: 99%

Effect of a Novel Immunosuppressant, FTY720, on Allograft Survival after Renal Transplant in Rats

et al. 2000

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FTY720 was developed by chemical modification of ISP-1 which was purified from culture filtrates of an ascomycete, Isaria sinclairii. We evaluated the effect of FTY720 on allograft survival using a rat renal transplantation model in which Wistar King Aptekman Hokkaido rats (WKAH, RT1^K) served as the organ donor and Lewis rats (LEW, RT1^l) as the recipient. WKAH renal allografts were acutely rejected by the untreated LEW recipients at a mean graft survival ± SD of 7.2 ± 0.4 days (n = 5). Consecutive oral administration of FTY720 following transplantation significantly prolonged allograft survival in a dose-dependent manner over the range of 0.05–3 mg/kg/day. The mean allograft survival of the recipients treated with FTY720 at a doses of 0.05, 0.1, 0.5, 1, and 3 mg/kg/day was 12.2 ± 3.3 (n = 5, p < 0.05, vs. untreated host), 11.2 ± 2.4 (n = 5, p < 0.05, vs. untreated host), 13.6 ± 0.9 (n = 5, p < 0.01, vs. untreated host), 14.6 ± 1.7 (n = 5, p < 0.01, vs. untreated host) and 20.2 ± 0.8 days (n = 5, p < 0.01, vs. untreated host). In the recipients treated with FTY720 (3 mg/kg/day), the number of peripheral blood lymphocytes significantly decreased. From the results of the flow cytometric study, FTY720 significantly diminished the percentage of interleukin-2 receptor (IL-2R)-positive cells in the allografts (6.34 ± 0.81% in the untreated recipients vs. 3.10 ± 0.86% in the recipients treated with FTY720, p < 0.05). As to the CD4/CD8 ratio of splenic cells and graft infiltrate, there was no significant difference between the untreated hosts and the recipients treated with FTY720. In conclusion, FTY720 significantly extended rat renal allograft survival and the immunosuppressive effects of FTY720 may be due to a reduction in not only the number of peripheral lymphocytes but also the percentage of IL-2R-positive cells in the allografts.

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“…This immunomodulator is effective in protecting solid organ grafts from acute rejection in experimental transplant models (5). FTY720 is effective even in the absence of cyclosporine, and also shows synergistic interactions with cyclosporine, tacrolimus, sirolimus, or everolimus (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Fty720 (2-amino-2-[2-(4-octylphenyl)mentioning

confidence: 99%

“…The surrogate marker of the pharmacodynamic effect of FTY720 used in this study was the peripheral lymphocyte count in the blood compartment. Lymphocyte counts were performed on the occasion of each study visit (pretransplant and 1, 2, 4, 5,6,7,8,9,10,11,12,16,20, and 24 weeks after transplant) in all 5 groups using the CELL-DYN 3200 automatic counter (Abbott Park, Chicago, IL, USA) whose methods of determinations are based on flow cytometry. Since MMF has no effect on peripheral lymphocytes (25), lymphocyte counts obtained from patients receiving MMF were used to calculate the basal pharmacodynamic effect when FTY720 doses or exposures were equal to zero.…”

Section: Pharmacokinetics/pharmacodynamicsmentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

Park

Felipe

Machado

et al. 2005

Braz J Med Biol Res

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FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r 2 = 0.98) and showed low inter-and intraindividual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple E max model [E = (E max * C)/(C + EC 50 )] was the best-fit PK/PD modeling for FTY720 dose (E max = 87.8 ± 5.3% and ED 50 = 0.48 ± 0.08 mg, r 2 = 0.94) or concentration (E max = 78.3 ± 2.9% and EC 50 = 0.59 ± 0.09 ng/ml, r 2 = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an E max model (EC 50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.

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Preclinical evaluation of a new immunosuppressive agent, FTY720

Cited by 25 publications

References 12 publications

No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation

No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation

Effect of a Novel Immunosuppressant, FTY720, on Allograft Survival after Renal Transplant in Rats

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

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