Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study

Kahan, Barry D.; Karlix, Janet L.; Ferguson, Ronald M.; Leichtman, Alan B.; Mulgaonkar, Shamkant; Gonwa, Thomas A.; Skerjanec, Andrej; Schmouder, Robert; Chodoff, Lawrence

doi:10.1097/01.tp.0000084822.01372.ac

Cited by 122 publications

(92 citation statements)

References 21 publications

(16 reference statements)

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“…4 Disruption of the S1P gradient therefore negates a major mechanism for stimulating the movement of lymphocytes from lymph nodes to the peripheral blood and results in a marked lymphopenia. [5][6][7] As such, FTY720 has undergone trials for the prevention of graft rejection for renal transplantation [8][9][10][11][12][13] and for the treatment of autoimmune disorders such as multiple sclerosis, although only the latter application remains viable at this point in time.…”

Section: Introductionmentioning

confidence: 99%

FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells

Wallington-Beddoe¹,

Hewson²,

Bradstock³

et al. 2011

Autophagy

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Section: Introductionmentioning

confidence: 99%

FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells

Wallington-Beddoe¹,

Hewson²,

Bradstock³

et al. 2011

Autophagy

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“…This mechanism of action has been shown to be highly effective in suppressing allograft rejection and autoimmune diseases in a variety of animal models [4,5] and in initial clinical trials [6,7]. As a synthetic analog of the lysophospholipid sphingosine 1-phosphate (S1P), phosphorylated FTY720 (FTY720-P) targets and activates G protein-coupled S1P receptors (S1PR), which are well characterized for their prominent functions in regulating growth-related and cytoskeleton-dependent cellular activities [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

et al. 2005

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The potent immunomodulator FTY720 elicits immunosuppression via acting on sphingosine 1-phosphate receptors (S1PR), thereby leading to an entrapment of lymphocytes in the secondary lymphoid tissue. To elucidate the potential in vitro effects of this drug on human monocyte-derived DC, we used low nanomolar therapeutic concentrations of FTY720 and phosphorylated FTY720 (FTY720-P) and investigated their influence on DC surface marker expression, protein levels of S1PR and DC effector functions: antigen uptake, chemotaxis, cytokine production, allostimulatory and Thpriming capacity. We report that both FTY720 and FTY720-P reduce chemotaxis of immature and mature DC. Mature DC generated in the presence of FTY720 or FTY720-P showed an impaired immunostimmulatory capacity and reduced IL-12 but increased IL-10 production. T cells cultured in the presence of FTY720-or FTY720-P-treated DC showed an altered cytokine production profile indicating a shift from Th1 toward Th2 differentiation. In treated immature and mature DC, expression levels for two S1PR proteins, S1P 1 and S1P 4, were reduced. We conclude that in vitro treatment with FTY720 affects DC features that are essential for serving their role as antigen-presenting cells. This might represent a new aspect of the overall immunosuppressive action of FTY720 and makes DC potential targets of further sphingolipid-derived drugs.

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“…Furthermore, FTY720 at doses up to 5 mg has been shown to be well tolerated in renal transplant recipients (9) and does not appear to be associated with the nephrotoxicity and side effects on the central…”

Section: Introductionmentioning

confidence: 99%

FTY720/Cyclosporine Regimens in De Novo Renal Transplantation: A 1-Year Dose-Finding Study

Mulgaonkar

Tedesco

Oppenheimer

et al. 2006

American Journal of Transplantation

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FTY720 is a novel immunomodulator being investigated for rejection prophylaxis in renal transplantation when combined with full-dose cyclosporine (CsA; FDC). This 1-year phase II study compared FTY720 plus FDC (Neoral ® ) with FTY720 plus reduced-dose CsA (RDC) and mycophenolate mofetil (MMF) plus FDC in de novo renal transplant patients. Patients were randomized 2:2:2:1 to FTY720 5 mg plus RDC (n = 72); FTY720 2.5 mg plus RDC (n = 74); FTY720 2.5 mg plus FDC (n = 76); or MMF plus FDC (n = 39) for 12 months. CsA exposure in the RDC group was reduced on average by 50% as assessed by C 2 monitoring. The primary efficacy endpoint was the composite incidence of biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation. The incidences for this composite endpoint were 24% and 22%, respectively, for FTY720 5 mg plus RDC and FTY720 2.5 mg plus FDC versus 39% for MMF plus FDC. Patients receiving FTY720 2.5 mg plus RDC were discontinued from treatment due to risk of under-immunosuppression. FTY720 2.5 mg plus FDC and FTY720 5 mg plus RDC were safe and effective in de novo renal transplant patients over 12 months.

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Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study

Cited by 122 publications

References 21 publications

FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells

FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

FTY720/Cyclosporine Regimens in De Novo Renal Transplantation: A 1-Year Dose-Finding Study

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