Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C19H33NO2.C12H26O4S |
| Molecular Weight | 573.868 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CCCCCCCCCCCCOS(O)(=O)=O.CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1
InChI
InChIKey=XTLZVNMZICNQBB-UHFFFAOYSA-N
InChI=1S/C19H33NO2.C12H26O4S/c1-2-3-4-5-6-7-8-17-9-11-18(12-10-17)13-14-19(20,15-21)16-22;1-2-3-4-5-6-7-8-9-10-11-12-16-17(13,14)15/h9-12,21-22H,2-8,13-16,20H2,1H3;2-12H2,1H3,(H,13,14,15)
Fingolimod (FTY720) is a sphingosine 1-phosphate receptor modulator indicated and approved for the treatment of relapsing-remitting multiple sclerosis. Fingolimod (trade name Gilenya, Novartis) is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate
is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3,
4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of
lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is
unknown, but may involve reduction of lymphocyte migration into the central nervous system. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26715391 | https://www.ncbi.nlm.nih.gov/pubmed/23518370
Curator's Comment: Fingolimod crosses the blood–brain barrier (BBB) and accumulates in the CNS.
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
| 0.84 µM [IC50] | |||
| 2.1 µM [IC50] | |||
| 0.3 nM [EC50] | |||
| 0.3 nM [EC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | GILENYA Approved UseGILENYA is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. GILENYA is a sphingosine 1-phosphate receptor modulator indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. (1) Launch Date2010 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
0.65 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22149256 |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
FINGOLIMOD plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
149 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22149256 |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
FINGOLIMOD plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
7 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22149256 |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
FINGOLIMOD plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
Doses
| Dose | Population | Adverse events |
|---|---|---|
14 mg single, oral Overdose Dose: 14 mg Route: oral Route: single Dose: 14 mg Co-administed with:: phenoxymethylpenicillin(2000 mg, single) Sources: |
unhealthy, 33 years n = 1 Health Status: unhealthy Condition: multiple sclerosis Age Group: 33 years Sex: F Population Size: 1 Sources: |
Other AEs: Bradycardia, Hypotension... Other AEs: Bradycardia (1 patient) Sources: Hypotension (1 patient) |
1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
Other AEs: Appendicitis, Urinary tract infection... Other AEs: Appendicitis (serious, 1 patient) Sources: Urinary tract infection (serious, 1 patient) Hyperlipidemia (10.9%) Leukopenia (10.9%) Lymphopenia (17.4%) Constipation (4.3%) Diarrhea (13%) Stomatitis (13%) Alanine aminotransferase increased (2.2%) Aspartate aminotransferase increased (2.2%) Cystitis (15.2%) Bronchitis (4.3%) |
0.5 mg 1 times / day multiple, oral Recommended Dose: 0.5 mg, 1 times / day Route: oral Route: multiple Dose: 0.5 mg, 1 times / day Sources: |
unhealthy, 37 years n = 425 Health Status: unhealthy Condition: relapsing remitting MS Age Group: 37 years Sex: M+F Population Size: 425 Sources: |
Disc. AE: Transaminases increased... AEs leading to discontinuation/dose reduction: Transaminases increased (3.8%) Sources: |
3.5 mg single, oral Highest studied dose |
unhealthy, 43.2 years n = 3 Health Status: unhealthy Age Group: 43.2 years Sex: M+F Population Size: 3 Sources: |
Other AEs: Bradycardia, Carbon monoxide diffusing capacity decreased... Other AEs: Bradycardia (2 patients) Sources: Carbon monoxide diffusing capacity decreased (1 patient) Electrocardiogram T wave abnormal (1 patient) |
40 mg single, oral Overdose Dose: 40 mg Route: oral Route: single Dose: 40 mg Sources: |
unhealthy n = 6 Health Status: unhealthy Population Size: 6 Sources: |
Other AEs: Chest tightness... Other AEs: Chest tightness (mild, 5 patients) Sources: |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Bradycardia | 1 patient | 14 mg single, oral Overdose Dose: 14 mg Route: oral Route: single Dose: 14 mg Co-administed with:: phenoxymethylpenicillin(2000 mg, single) Sources: |
unhealthy, 33 years n = 1 Health Status: unhealthy Condition: multiple sclerosis Age Group: 33 years Sex: F Population Size: 1 Sources: |
| Hypotension | 1 patient | 14 mg single, oral Overdose Dose: 14 mg Route: oral Route: single Dose: 14 mg Co-administed with:: phenoxymethylpenicillin(2000 mg, single) Sources: |
unhealthy, 33 years n = 1 Health Status: unhealthy Condition: multiple sclerosis Age Group: 33 years Sex: F Population Size: 1 Sources: |
| Hyperlipidemia | 10.9% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Leukopenia | 10.9% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Diarrhea | 13% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Stomatitis | 13% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Cystitis | 15.2% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Lymphopenia | 17.4% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Alanine aminotransferase increased | 2.2% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Aspartate aminotransferase increased | 2.2% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Bronchitis | 4.3% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Constipation | 4.3% | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Appendicitis | serious, 1 patient | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Urinary tract infection | serious, 1 patient | 1.25 mg 1 times / day steady, oral Highest studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: steady Dose: 1.25 mg, 1 times / day Sources: |
unhealthy, 36.0 years (range: 18–55 years) n = 46 Health Status: unhealthy Condition: relapsing multiple sclerosis Age Group: 36.0 years (range: 18–55 years) Sex: M+F Population Size: 46 Sources: |
| Transaminases increased | 3.8% Disc. AE |
0.5 mg 1 times / day multiple, oral Recommended Dose: 0.5 mg, 1 times / day Route: oral Route: multiple Dose: 0.5 mg, 1 times / day Sources: |
unhealthy, 37 years n = 425 Health Status: unhealthy Condition: relapsing remitting MS Age Group: 37 years Sex: M+F Population Size: 425 Sources: |
| Carbon monoxide diffusing capacity decreased | 1 patient | 3.5 mg single, oral Highest studied dose |
unhealthy, 43.2 years n = 3 Health Status: unhealthy Age Group: 43.2 years Sex: M+F Population Size: 3 Sources: |
| Electrocardiogram T wave abnormal | 1 patient | 3.5 mg single, oral Highest studied dose |
unhealthy, 43.2 years n = 3 Health Status: unhealthy Age Group: 43.2 years Sex: M+F Population Size: 3 Sources: |
| Bradycardia | 2 patients | 3.5 mg single, oral Highest studied dose |
unhealthy, 43.2 years n = 3 Health Status: unhealthy Age Group: 43.2 years Sex: M+F Population Size: 3 Sources: |
| Chest tightness | mild, 5 patients | 40 mg single, oral Overdose Dose: 40 mg Route: oral Route: single Dose: 40 mg Sources: |
unhealthy n = 6 Health Status: unhealthy Population Size: 6 Sources: |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
Drug as perpetrator
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
Page: (ClinPharm) 11, 54, 55, 56-57, 207-210 |
minor [Km 107 uM] | unlikely (co-administration study) Comment: Recombinant human CYP3A4, Vmax = 1423 pmol/(min.nmol CYP); Cyclosporine did not modify fingolimod overall exposure AUC(0-tz) or peak concentration (Cmax). The pharmacokinetics of steady-state cyclosporine were not altered during coadministration with singledose fingolimod. Page: (ClinPharm) 11, 54, 55, 56-57, 207-210 |
||
| minor [Km 73 uM] | ||||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022527Orig1s000clinpharmr.pdf#page=89 Page: (ClinPharm) 89 |
no | |||
| yes [Km 117 uM] | ||||
| yes [Km 76 uM] |
Tox targets
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
PubMed
| Title | Date | PubMed |
|---|---|---|
| Coexpression of CD4 and CD8alpha on rat T-cells in whole blood: a sensitive marker for monitoring T-cell immunosuppressive drugs. | 2001 Aug 1 |
|
| Combined FTY720/cyclosporine A treatment promotes graft survival and lowers the peripheral lymphocyte count in DA to lewis heart and skin transplantation models. | 2001 Feb |
|
| FTY 720 prevents ischemic reperfusion damage in rat kidneys. | 2001 Feb-Mar |
|
| FTY720, a novel immunosuppressive agent with insulinotropic activity, prolongs graft survival in a mouse islet transplantation model. | 2001 Feb-Mar |
|
| Combined FTY720/cyclosporine treatment promotes graft survival and lowers the peripheral lymphocyte count in a murine cardiac allotransplantation model. | 2001 Jul 15 |
|
| A high-capacity quantitative mouse model of drug-mediated immunosuppression based on rejection of an allogeneic subcutaneous tumor. | 2001 Jun |
|
| Treatment of transplant rejection: are the traditional immunosuppressants good enough? | 2001 Mar |
|
| T-cell apoptosis triggered by FTY720 via mitochondrial pathway. | 2001 Nov-Dec |
|
| FTY720, a novel transplantation drug, modulates lymphocyte migratory responses to chemokines. | 2001 Nov-Dec |
|
| FTY720: altered lymphocyte traffic results in allograft protection. | 2001 Sep 15 |
|
| First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. | 2002 Apr |
|
| FTY720: a novel approach to the treatment of hepatic ischemia-reperfusion injury. | 2002 Aug |
|
| T cell selective apoptosis by a novel immunosuppressant, FTY720, is closely regulated with Bcl-2. | 2002 Dec |
|
| Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus. | 2002 Feb |
|
| L-selectin-dependent lymphoid occupancy is required to induce alloantigen-specific tolerance. | 2002 Feb 15 |
|
| What role for FTY720, a novel immunosuppressive agent, in canine nonmyeloablative hematopoietic stem cell transplantation? | 2002 Jan 27 |
|
| Combination treatment with FTY720 and CTLA4IgG preserves the respiratory epithelium and prevents obliterative disease in a murine airway model. | 2002 Jun |
|
| Anticarcinogenic effect of FTY720 in human prostate carcinoma DU145 cells: modulation of mitogenic signaling, FAK, cell-cycle entry and apoptosis. | 2002 Mar 10 |
|
| Combined use of FTY720 and cyclosporine A prevents chronic allograft vasculopathy. | 2002 May |
|
| Pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720) in cynomolgus monkeys after single oral and intravenous doses. | 2002 May |
|
| Long-term islet graft survival in streptozotocin- and autoimmune-induced diabetes models by immunosuppressive and potential insulinotropic agent FTY720. | 2002 May 15 |
|
| FTY720 pretreatment reduces warm hepatic ischemia reperfusion injury through inhibition of T-lymphocyte infiltration. | 2002 Oct |
|
| FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. | 2002 Oct |
|
| Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation, given alone or in combination with cyclosporine or RAD. | 2002 Oct 15 |
|
| Renal transplantation: basic concepts and evolution of therapy. | 2003 |
|
| A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells. | 2003 Apr |
|
| Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm. | 2003 Aug |
|
| Current immunosuppressive agents: efficacy, side effects, and utilization. | 2003 Dec |
|
| Inhibition of Th1- and Th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720. | 2003 Dec 1 |
|
| Pretreatment with FTY720 alone induced long-term survival of mouse heart allograft. | 2003 Feb |
|
| CTLA4Ig-gene transfection with FTY720 administration markedly inhibits the obliterative airway disease in heterotopically transplanted rat tracheas. | 2003 Feb |
|
| [Effects of three different immunosuppressive drugs on SD rat islet cell viability]. | 2003 Feb |
|
| Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. | 2003 Jul |
|
| New paradigms in immunosuppression. | 2003 Jul-Sep |
|
| The effect of FTY 720 on engraftment in a model of spontaneous allograft acceptance. | 2003 Jun |
|
| FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes. | 2003 Mar |
|
| Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. | 2003 Nov 28 |
|
| The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. | 2003 Nov 6 |
|
| [Study the mechanisms and inducing transplantation immune tolerance of FTY720]. | 2003 Oct |
|
| Egress: a receptor-regulated step in lymphocyte trafficking. | 2003 Oct |
|
| Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. | 2003 Oct 15 |
|
| FTY720 does not abrogate acute graft-versus-host disease in the dog leukocyte antigen-nonidentical unrelated canine model. | 2003 Oct 27 |
|
| CD4+ CD25+ CD62+ T-regulatory cell subset has optimal suppressive and proliferative potential. | 2004 Jan |
|
| Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. | 2004 Jan 22 |
|
| The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells. | 2004 Jun 15 |
|
| FTY720-induced lymphocyte homing modulates post-transplant preservation/reperfusion injury. | 2004 Mar |
|
| Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. | 2004 May |
Patents
Sample Use Guides
The recommended dose of GILENYA is 0.5 mg orally once-daily. Fingolimod doses higher than 0.5 mg are associated
with a greater incidence of adverse reactions without additional benefit. GILENYA can be taken with or without food.
Route of Administration:
Oral
Astrocytes derived from human fetal CNS specimens and maintained in dissociated cultures were exposed to 100 nM of the biologically active form of Fingolimod (FTY720) over a dosing regimen that ranged from a single exposure (with or without washout after 1 h) to daily exposures up to 5 days, a single addition of FTY720 inhibited subsequent S1PR ligand-induced pERK1/2 signaling for >24 h. Daily FTY720 treatments (3-5 days) maintained this effect together with a loss of proliferative responses to the natural ligand S1P. Repeated FTY720 dosing concurrently maintained a functional cell response as measured by the inhibition of intracellular calcium release when stimulated by the cytokine IL-1β. Recurrent FTY720 treatments did not inhibit serum- or IL-1β-induced pERK1/2.
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157010667
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J3HZQ9BE2S
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2610292
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J3HZQ9BE2S
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1967800-35-6
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ACTIVE MOIETY
SUBSTANCE RECORD
