fingolimod

fingolimod
IUPAC name	2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
Tradename	Gilenya, others
Drugs.com	Monograph
MedlinePlus	a611016
Licence US	Fingolimod
Routes of administration	By mouth
CAS number	162359-56-0
PubChem	107970
ChemSpiderID	97050
UNII	G926EC510T
ChEBI	63548
ChEMBL	1213480
ATC prefix	L04
ATC suffix	AA27

fingolimod is an immunomodulating medication primarily used for the treatment of relapsing forms of multiple sclerosis. It functions as a sphingosine 1-phosphate receptor modulator, effectively sequestering lymphocytes within lymph nodes to reduce central nervous system inflammation. Developed by the Swiss pharmaceutical company Novartis, it was the first oral disease-modifying therapy approved for multiple sclerosis by the U.S. Food and Drug Administration in 2010, marking a significant shift in the therapeutic landscape for the condition.

Medical uses

Fingolimod is indicated for the treatment of relapsing-remitting multiple sclerosis in adults and pediatric patients aged ten years and older, as established by clinical trials such as FREEDOMS and TRANSFORMS. It is also approved for clinically isolated syndrome in some regions, following evidence from the FREEDOMS II study. The medication is generally prescribed after an inadequate response to, or intolerance of, first-line therapies like interferon beta-1a or glatiramer acetate, though specific guidelines vary by national bodies like the National Institute for Health and Care Excellence. Its use requires careful patient selection and monitoring due to potential cardiovascular and infectious risks.

Mechanism of action

Fingolimod is a prodrug phosphorylated in vivo by sphingosine kinase to its active form, fingolimod phosphate. This active metabolite acts as a functional antagonist at sphingosine 1-phosphate receptors, specifically subtypes 1, 3, 4, and 5, with high affinity for the S1P receptor 1 subtype. By binding to these receptors on lymphocytes, it induces internalization and degradation, preventing the egress of T cells and B cells from secondary lymphoid organs like the lymph nodes and the thymus. This sequestration reduces the recirculation of autoreactive lymphocytes into the central nervous system and peripheral circulation, thereby attenuating the inflammatory attacks characteristic of multiple sclerosis.

Adverse effects

Common adverse effects include headache, influenza, diarrhea, back pain, liver enzyme elevations, and cough. Serious risks necessitate a six-hour observation period after the first dose due to potential bradycardia and atrioventricular block, as noted in the FDA label. Other significant concerns include increased susceptibility to infections like herpes zoster and progressive multifocal leukoencephalopathy, macular edema, hypertension, and a slight elevation in the risk of certain malignancies, particularly basal cell carcinoma. Regular monitoring of complete blood count, liver function tests, and ophthalmic examinations is mandated.

Pharmacokinetics

Following oral administration, fingolimod is well absorbed with a bioavailability of approximately 93%, reaching peak plasma concentrations within 12 to 16 hours. It is extensively distributed and highly bound to plasma proteins, primarily albumin. Metabolism occurs primarily via CYP4F2 and other enzymes to inactive metabolites, with a terminal elimination half-life of 6 to 9 days. The active phosphate metabolite has a half-life of approximately 30 days. Excretion is mainly through urine as inactive metabolites, with no need for dosage adjustment in mild hepatic impairment, though caution is advised in severe cases.

History and society

Fingolimod originated from research into fungal metabolites, specifically myriocin from the fungus Isaria sinclairii, by scientists at the Mitsubishi Tanabe Pharma Corporation. Its development for multiple sclerosis was later spearheaded by Novartis. The U.S. Food and Drug Administration approved it in September 2010 following review of data from the pivotal FREEDOMS trial, with the European Medicines Agency granting authorization in 2011. Its introduction prompted discussions on cost-effectiveness by bodies like the National Institute for Health and Care Excellence and influenced treatment paradigms, leading to the subsequent development of other S1P receptor modulators such as siponimod and ozanimod.

Research

Ongoing research explores the potential neuroprotective and reparative effects of fingolimod beyond immunomodulation, given the expression of S1P receptors on neural cells like astrocytes, oligodendrocytes, and neurons. Studies, including those published in journals like Nature Neuroscience, investigate its role in promoting remyelination and modulating astrocyte reactivity. Clinical trials have also examined its efficacy in other autoimmune conditions, such as systemic lupus erythematosus and rheumatoid arthritis, though with limited success to date. Further investigation continues into its long-term safety profile and potential use in pediatric populations and combination therapies.

Category:Drugs