Siponimod

Uses

Siponimod is a medication used to treat relapsing multiple sclerosis.

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 .

Siponimod is also used to associated treatment for these conditions: Relapsing Multiple Sclerosis (RMS)

How Siponimod works

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 . The S1P receptor is an important receptor related to the function of lymphocytes and can be found in the central nervous system . S1P receptor (S1PR) signaling is associated with a wide variety of physiological processes for lymphocytes, including their egress and recirculation .

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 .

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 .

Mutagenesis

Siponimod was negative in several in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays .

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 .

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 .

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 . No data currently exist regarding the presence of siponimod in human milk . 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 .

Food Interaction

• 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.

Siponimod Drug Interaction

Major: hydroxyzine, sotalolModerate: fluticasone / vilanterolMinor: sulfamethoxazole / trimethoprimUnknown: charcoal, phenazopyridine, calcium / vitamin d, ubiquinone, docusate, copper gluconate, estradiol topical, ethanol, omega-3 polyunsaturated fatty acids, fluticasone nasal, fluticasone, chondroitin / glucosamine / methylsulfonylmethane, heparin, vitamin a topical, bioflavonoids, cholecalciferol

Siponimod Disease Interaction

Major: cardiovascular diseaseModerate: encephalopathy, MS, infections, liver disease, macular edema, vaccinations

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 .

Elimination Route

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 .

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 .

Half Life

The apparent elimination half-life is approximately 30 hours .

Clearance

Apparent systemic clearance of 3.11 L/h has been estimated in MS patients .

Elimination Route

Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine .

Innovators Monograph

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