An oral sphingosine-1-phosphate-receptor modulator.
Following phosphorylation, fingolimod acts as a functional antagonist of the sphingosine-1-phosphate type 1 receptor, and causes T and B cells to be insensitive to signals needed for egress from lymphoid tissues.
An oral sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS) in patients 10 years of age and older.
Acts by preventing lymphocyte egress from lymph nodes (Mandala S).
May reduce infiltration into the central nervous system of potentially aggressive lymphocytes (Compsyon A).
In MS associated with a decrease in the total mean lymphocyte count and blocks the exit of naïve and central memory lymphocytes, but not effector memory T cells from the lymph node.
Naïve T cells and central memory cells, but not effector memory cells, express the chemokine receptor CCR7, which induces homing to the lymph nodes.
Part of this agent’s therapeutic action may be independent of its effect on peripheral lymphocytes.
This agent is lipophilic and readily crosses the blood brain barrier, where it is phosphorylated in the CNS (Foster CA).
It is administered once daily, with a recommended dosage of 0.5 mg for adults and pediatric patients weighing more than 40 kg, and 0.25 mg for pediatric patients weighing 40 kg or less.
Fingolimod is metabolized to its active form, fingolimod-phosphate, which binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5, blocking lymphocyte egress from lymph nodes and reducing peripheral blood lymphocyte counts.
Laboratory testing indicates that this agent may protect neurologic tissue and promote repair processes within the CNS via modulation of sphingosine-1-phosphate-receptors expressed on neurons.
The precise mechanism by which fingolimod exerts its therapeutic effects in MS is not fully understood but may involve reduced lymphocyte migration into the central nervous system.
Cardiovascular effects of felt to be due to binding of the drug to sphingosine-1-phosphate receptors in cardiac muscle.
First-dose monitoring is required due to the risk of bradycardia and atrioventricular conduction delays at treatment initiation.
Can cross the blood brain barrier and bindss to S1P1,S3, and S1P5 receptors on neural cells.
S1P1 and S1P3 receptors are strongly expressed in multiple sclerosis lesions, and expression of these receptors is associated with astrogliosis, a main pathological feature of multiple sclerosis lesions.
Treatment can reduce neuroinflammatory disease and improve CNS tissue integrity.
The anti-inflammatory effects of this drug does not slow disease progression in primary progressive multiple sclerosis (Lubli ).
In large, randomized controlled trials, where it significantly reduced annualized relapse rates, MRI lesion activity, and slowed disability progression compared to both placebo and intramuscular interferon-β-1a.
Its mechanism involves functional antagonism of sphingosine 1-phosphate (S1P) receptors, particularly S1P\(_1\), leading to sequestration of lymphocytes in lymph nodes and a reduction in their migration into the central nervous system, thereby limiting autoimmune-mediated inflammation.
Fingolimod also crosses the blood-brain barrier and may exert direct effects on neural cells, including astrocytes, oligodendrocytes, and neurons, which could contribute to neuroprotective and reparative processes in MS.
While its immunomodulatory action is central to its benefit, this mechanism also underlies risks such as lymphopenia and increased susceptibility to infections, including rare but serious opportunistic infections.
Cardiac monitoring is required at initiation due to the risk of bradycardia and atrioventricular block, which are attributed to S1P receptor modulation in cardiac tissue.