Siponimod
Identification
- Summary
Siponimod is a medication used to treat relapsing multiple sclerosis.
- Brand Names
- Mayzent 0.25 Mg Starter Pack
- Generic Name
- Siponimod
- DrugBank Accession Number
- DB12371
- Background
Siponimod, also known as Mayzent, by Novartis, is a new drug formulated for the management of Multiple Sclerosis (MS). It was approved by the FDA on March 26, 2019 6 and by Health Canada on February 20, 2020.8 This drug is considered a sphingosine-1-phosphate (S1P) receptor modulator and is thought to play a role in suppressing the central nervous system inflammation that is associated with MS Label.
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system that is chronic and inflammatory, disrupting communication between the brain and other parts of the body. Most patients diagnosed with this illness experience their initial disease symptoms between the age of 20 to 40, often the most productive years of life. Symptoms may include but are not limited to fatigue, gait changes, bowel or bladder dysfunction, abnormal muscle twitching, vision disturbance, and depressing or mood swings.7 MS is one of the most common causes of neurological disability in young adults and is found to occur more frequently in women than in men.1,6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 516.605
Monoisotopic: 516.259977484 - Chemical Formula
- C29H35F3N2O3
- Synonyms
- Siponimod
- External IDs
- BAF-312
- BAF312
- NVP-BAF312-NX
Pharmacology
- Indication
This drug is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults Label.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Relapsing multiple sclerosis (rms) •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Immune system effects
Siponimod causes a dose-dependent decrease of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by the reversible accumulation of lymphocytes in lymphoid tissues, due to lack of lymphocyte release Label. This results in a decrease in the inflammation that is involved in multiple sclerosis. Lymphocyte counts return to normal in 90% of patients within 10 days after the cessation of therapy Label.
Effects on heart rate and rhythm
Siponimod causes a temporary decrease in heart rate and atrioventricular conduction upon beginning treatment. The maximum fall in heart rate is observed in the first 6 hours post ingestion. Autonomic heart responses, including diurnal variation of heart rate and response to exercise activities, are not altered by siponimod treatment Label.
Effects on pulmonary function
Dose-dependent decreases in absolute forced expiratory volume over a time frame of 1 second were noted in siponimod-treated patients and were higher than in patients taking placebo Label.
- Mechanism of action
Inflammation of the white and gray matter tissues in the central nervous system caused by localized immune cell infiltration and their cytokines are the initial cause of damage in MS. B lymphocytes and their cytokines are other factors in the pathogenesis of MS. Lymphotoxin [or transforming growth factor beta (TGF-β)] and TNF-α produced by these cells encourage inflammation 1. The S1P receptor is an important receptor related to the function of lymphocytes and can be found in the central nervous system 4. S1P receptor (S1PR) signaling is associated with a wide variety of physiological processes for lymphocytes, including their egress and recirculation 2,3.
Siponimod is classified as a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to both S1P receptors 1 and 5. This drug blocks the ability of lymphocytes to release from the lymph nodes, decreasing the number of lymphocytes found in the peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is not known at this time, but may involve the abovementioned decrease of lymphocytes into the central nervous system, decreasing the inflammatory effects of MS Label.
Target Actions Organism USphingosine 1-phosphate receptor 5 modulatorHumans USphingosine 1-phosphate receptor 1 Not Available Humans - Absorption
The time (Tmax) to attain maximum plasma concentrations (Cmax) after oral administration of immediate-release oral doses of siponimod was found to be approximately 4 hours ( with a range 3 - 8 hours). Siponimod is heavily absorbed (at a rate greater than or equal to 70%). The absolute oral bioavailability of siponimod is about 84%. Steady-state concentrations were attained after approximately 6 days of daily administration of a single dose of siponimod Label.
Effects of food on absorption
Food ingestion leads to delayed siponimod absorption (the median Tmax increased by approximately 2-3 hours). Food intake has no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, siponimod may be taken without regard to food Label.
- Volume of distribution
Siponimod distributes to body tissues with an average volume of distribution of 124 L. Siponimod fraction mesaured in plasma is 68% in humans. Animal studies demonstrate that siponimod readily crosses the blood-brain-barrier Label.
- Protein binding
Protein binding of siponimod is higher than 99.9% in healthy patients as well as hepatic and renal impaired patients Label.
Because of the high plasma protein binding of siponimod, hemodialysis is not likely to change the total and unbound siponimod concentration and no dose adjustments are expected based on this Label.
- Metabolism
Siponimod is extensively metabolized, mainly by CYP2C9 enzyme (79.3%), and subsequently by CYP3A4 enzyme (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to be responsible for the clinical effect and the safety of siponimod in humans Label.
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- Route of elimination
Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine Label.
- Half-life
The apparent elimination half-life is approximately 30 hours Label.
- Clearance
Apparent systemic clearance of 3.11 L/h has been estimated in MS patients Label.
- Adverse Effects
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- Toxicity
Carcinogenesis
Oral carcinogenicity studies of siponimod were performed in mice and rats. There was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day Label.
Mutagenesis
Siponimod was negative in several in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays Label.
Impairment of fertility
When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) before and throughout the mating period, there was a dose-related increase in the precoital interval at any dose. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were noted at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the recommended human dose Label.
When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were noted up to the highest dose studied (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose studied is about 16 times that in humans at the recommended human dose Label.
Use in pregnancy and lactation
Siponimod may cause fetal harm, based on the results of animal studies. Because it takes about 10 days to eliminate this drug from the body, women of childbearing potential should use adequate contraception to avoid pregnancy during and for 10 days after the cessation of treatment Label. No data currently exist regarding the presence of siponimod in human milk Label. A study in lactating rats demonstrated excretion of the drug and/or its metabolites in milk. The benefits nursing should be considered as well as the mother’s clinical requirement for this drug and any possible adverse effects on the breastfed infant from siponimod Label.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Siponimod can be increased when it is combined with Abametapir. Abatacept The metabolism of Siponimod can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Siponimod. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Siponimod. Acalabrutinib The metabolism of Siponimod can be decreased when combined with Acalabrutinib. - Food Interactions
- Avoid St. John's Wort. Avoid the use of St. John's wort in patients with CYP2C9 genotype *1/*3 and*2/*3.
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Siponimod fumarate Z7G02XZ0M6 1234627-85-0 JNLIKIBISICTMS-PEJBKAKVSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Mayzent Tablet, film coated 2 mg Oral Novartis Europharm Limited 2020-12-16 Not applicable EU Mayzent Tablet, film coated 0.25 mg Oral Novartis Europharm Limited 2020-12-16 Not applicable EU Mayzent Tablet, film coated 1 mg/1 Oral Novartis Pharmaceuticals Corporation 2019-03-26 Not applicable US Mayzent Tablet, film coated 2 mg/1 Oral Novartis Pharmaceuticals Corporation 2019-03-26 Not applicable US Mayzent Tablet, film coated 1 mg Oral Novartis Europharm Limited 2022-05-04 Not applicable EU
Categories
- ATC Codes
- L04AA42 — Siponimod
- Drug Categories
- Agents that produce hypertension
- Antineoplastic and Immunomodulating Agents
- Azetines
- Benzene Derivatives
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Immunologic Factors
- Immunomodulatory Agents
- Immunosuppressive Agents
- Immunotherapy
- Narrow Therapeutic Index Drugs
- Receptors, Lysosphingolipid, antagonists & inhibitors
- Selective Immunosuppressants
- Sphingosine 1 Phosphate Receptor Modulators
- Sphingosine 1-phosphate Receptor Modulator
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as trifluoromethylbenzenes. These are organofluorine compounds that contain a benzene ring substituted with one or more trifluoromethyl groups.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Trifluoromethylbenzenes
- Direct Parent
- Trifluoromethylbenzenes
- Alternative Parents
- Phenylmethylamines / Benzylamines / Azetidinecarboxylic acids / Aralkylamines / Trialkylamines / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds show 5 more
- Substituents
- Alkyl fluoride / Alkyl halide / Amine / Amino acid / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Azetidine / Azetidinecarboxylic acid show 19 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- RR6P8L282I
- CAS number
- 1230487-00-9
- InChI Key
- KIHYPELVXPAIDH-HNSNBQBZSA-N
- InChI
- InChI=1S/C29H35F3N2O3/c1-3-21-14-23(10-11-24(21)15-34-16-25(17-34)28(35)36)19(2)33-37-18-20-9-12-26(22-7-5-4-6-8-22)27(13-20)29(30,31)32/h9-14,22,25H,3-8,15-18H2,1-2H3,(H,35,36)/b33-19+
- IUPAC Name
- 1-({4-[(1E)-1-({[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy}imino)ethyl]-2-ethylphenyl}methyl)azetidine-3-carboxylic acid
- SMILES
- CCC1=CC(=CC=C1CN1CC(C1)C(O)=O)C(\C)=N\OCC1=CC=C(C2CCCCC2)C(=C1)C(F)(F)F
References
- General References
- Ghasemi N, Razavi S, Nikzad E: Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. Epub 2016 Dec 21. [Article]
- Chiba K, Matsuyuki H, Maeda Y, Sugahara K: Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol. 2006 Feb;3(1):11-9. [Article]
- Garris CS, Blaho VA, Hla T, Han MH: Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology. 2014 Jul;142(3):347-53. doi: 10.1111/imm.12272. [Article]
- Healy LM, Antel JP: Sphingosine-1-Phosphate Receptors in the Central Nervous and Immune Systems. Curr Drug Targets. 2016;17(16):1841-1850. [Article]
- Dumitrescu L, Constantinescu CS, Tanasescu R: Siponimod for the treatment of secondary progressive multiple sclerosis. Expert Opin Pharmacother. 2019 Feb;20(2):143-150. doi: 10.1080/14656566.2018.1551363. Epub 2018 Dec 5. [Article]
- FDA approves new oral drug to treat multiple sclerosis [Link]
- MS Society Document, Canada [Link]
- Health Canada Product Monograph: Mayzent (siponimod) oral tablets [Link]
- External Links
- PubChem Compound
- 44599207
- PubChem Substance
- 347828622
- ChemSpider
- 29315058
- BindingDB
- 50428142
- 2121085
- ChEMBL
- CHEMBL2336071
- ZINC
- ZINC000006717453
- Wikipedia
- Siponimod
- FDA label
- Download (982 KB)
- MSDS
- Download (22.4 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Coronavirus Disease 2019 (COVID‑19) / Secondary Progressive Multiple Sclerosis (SPMS) 1 4 Recruiting Treatment Relapsing Remitting Multiple Sclerosis (RRMS) 1 3 Completed Treatment Advancing Multiple Sclerosis / Multiple Sclerosis / Relapsing Multiple Sclerosis (RMS) 1 3 Completed Treatment Secondary Progressive Multiple Sclerosis (SPMS) 1 3 Recruiting Treatment Multiple Sclerosis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 0.25 mg Tablet Oral 0.278 mg Tablet Oral 1 mg Tablet Oral 2 mg Tablet, film coated Oral 0.25 mg/1 Tablet, film coated Oral 1 mg Tablet, film coated Oral 1 mg/1 Tablet, film coated Oral 2 mg/1 Tablet, film coated Oral 0.25 mg Tablet, film coated Oral 2 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8492441 No 2013-07-23 2030-11-30 US US7939519 No 2011-05-10 2024-05-19 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 111-112 https://www.trc-canada.com/product-detail/?CatNum=S487800&CAS=342026-92-0&Chemical_Name=Sipoglitazar&Mol_Formula=C₂₅H₂₅N₃O₄S boiling point (°C) 419 https://comptox.epa.gov/dashboard/dsstoxdb/calculation_details?model_id=27&search=153847 water solubility 100 mg/mL , warm water https://www.selleckchem.com/products/baf312-siponimod.html logP 6.77 https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2336071/ pKa 2.69 (Acidic), 9.15 (Basic) https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2336071/ - Predicted Properties
Property Value Source Water Solubility 0.00032 mg/mL ALOGPS logP 5.85 ALOGPS logP 4.31 Chemaxon logS -6.2 ALOGPS pKa (Strongest Acidic) 3.33 Chemaxon pKa (Strongest Basic) 8.5 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 62.13 Å2 Chemaxon Rotatable Bond Count 10 Chemaxon Refractivity 138.6 m3·mol-1 Chemaxon Polarizability 55.99 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 209.99857 predictedDeepCCS 1.0 (2019) [M+H]+ 212.39412 predictedDeepCCS 1.0 (2019) [M+Na]+ 218.30664 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Modulator
- General Function
- Sphingosine-1-phosphate receptor activity
- Specific Function
- Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both...
- Gene Name
- S1PR5
- Uniprot ID
- Q9H228
- Uniprot Name
- Sphingosine 1-phosphate receptor 5
- Molecular Weight
- 41774.515 Da
References
- Gajofatto A: Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date. Drug Des Devel Ther. 2017 Nov 2;11:3153-3157. doi: 10.2147/DDDT.S122249. eCollection 2017. [Article]
- Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A: Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013. doi: 10.1124/dmd.117.079574. Epub 2018 May 7. [Article]
- O'Sullivan C, Schubart A, Mir AK, Dev KK: The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflammation. 2016 Feb 8;13:31. doi: 10.1186/s12974-016-0494-x. [Article]
- Siponimod FDA label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Sphingosine-1-phosphate receptor activity
- Specific Function
- G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activatio...
- Gene Name
- S1PR1
- Uniprot ID
- P21453
- Uniprot Name
- Sphingosine 1-phosphate receptor 1
- Molecular Weight
- 42810.195 Da
References
- Pan S, Gray NS, Gao W, Mi Y, Fan Y, Wang X, Tuntland T, Che J, Lefebvre S, Chen Y, Chu A, Hinterding K, Gardin A, End P, Heining P, Bruns C, Cooke NG, Nuesslein-Hildesheim B: Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett. 2013 Jan 4;4(3):333-7. doi: 10.1021/ml300396r. eCollection 2013 Mar 14. [Article]
- Gianguzza M, Dolcemascolo G: On the ultrastructure of the test cells of Ascidia malaca during oogenesis. Acta Embryol Exp (Palermo). 1979;(2):173-89. [Article]
- Gajofatto A: Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date. Drug Des Devel Ther. 2017 Nov 2;11:3153-3157. doi: 10.2147/DDDT.S122249. eCollection 2017. [Article]
- Siponimod FDA label [File]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A: Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013. doi: 10.1124/dmd.117.079574. Epub 2018 May 7. [Article]
- Siponimod FDA label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A: Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013. doi: 10.1124/dmd.117.079574. Epub 2018 May 7. [Article]
- Siponimod FDA label [File]
Drug created at October 20, 2016 22:06 / Updated at November 01, 2023 04:05