Zeposia

Uses

Zeposia is a sphingosine 1-phosphate receptor modulator being studied to treat Multiple Sclerosis (MS) and inflammatory bowel disease (IBD).

Zeposia is indicated for adults in the treatment of relapsing forms of MS, which may include relapsing-remitting disease, clinically isolated syndrome, and active secondary progressive MS.

Zeposia is also used to associated treatment for these conditions: Clinically Isolated Syndrome (CIS), Progressive Multiple Sclerosis (PMS), Relapsing Forms of Multiple Sclerosis, Relapsing Remitting Multiple Sclerosis (RRMS)

How Zeposia works

Sphingosine‐1‐phosphate (S1P) is an important phospholipid that binds to various G‐protein‐coupled receptor subtypes, which can be identified as S1P1–5R. S1P and the receptors it binds to perform regular functions in the immune, cardiovascular, pulmonary, and nervous system. S1P can be expressed ubiquitously, playing an important role in regulating inflammation. S1P1R, S1P2R, and S1P3R receptors can be found in the cardiovascular, immune, and central nervous systems. S1P4R is found on lymphocytic and hematopoietic cells, while S1P5R expression is found only on the spleen (on natural killer cells) or in the central nervous system.

Zeposia is a selective modulator of S1P receptors and binds to S1P1R and S1P5R subtypes. The mechanism of action of ozanimod is not fully understood, but this drug likely reduces the migration of lymphocytes that usually aggravate the inflammation associated with MS.

Toxicity

Overdose and LD50 information for ozanimod is not readily available in the literature. The NOAEL dose is 0.164 mg/kg/d for monkeys, and the human equivalent dose to this is about 0.053 mg/kg/day. An overdose of this drug likely results in adverse effects such as somnolence, fatigue, headache, dizziness, bradyarrhythmia, cardiac conduction defects, hypertension, liver injury, and nausea.

Food Interaction

• Avoid tyramine-containing foods and supplements. Avoid food containing high amounts of tyramine (>150mg) as these may increase the risk of hypertension when taken with ozanimod.
• Take with or without food.

[Major] GENERALLY AVOID: Foods that contain large amounts of tyramine may precipitate a hypertensive crisis in patients treated with ozanimod.

The mechanism is inhibition of monoamine oxidase type A (MAO-A) by metabolites of ozanimod.

MAO-A is the enzyme responsible for metabolizing exogenous amines such as tyramine in the gut and preventing them from being absorbed intact.

Once absorbed, tyramine is metabolized to octopamine, a substance that is believed to displace norepinephrine from storage granules.

MANAGEMENT: In general, patients treated with ozanimod should avoid consumption of products that contain large amounts of amines (e.g., tyramine) and protein foods in which ageing or breakdown of protein is used to increase flavor.

These foods include cheese (particularly strong, aged or processed cheeses), sour cream, wine (particularly red wine), champagne, beer, pickled herring, anchovies, caviar, shrimp paste, liver (particularly chicken liver), dry sausage, salamis, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, sauerkraut, yogurt, papaya products, meat tenderizers, fava bean pods, protein extracts, yeast extracts, and dietary supplements.

Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well.

At least 14 days should elapse following discontinuation of ozanimod therapy before these foods may be consumed.

Specially designed reference materials and dietary consultation are recommended so that an appropriate and safe diet can be planned.

Patients should be advised to promptly seek medical attention if they experience potential signs and symptoms of a hypertensive crisis such as severe headache, visual disturbances, difficulty thinking, stupor or coma, seizures, chest pain, unexplained nausea or vomiting, and stroke-like symptoms.

Zeposia Hypertension interaction

[Moderate] The use of ozanimod may result in increased blood pressure.

Care should be exercised when using this drug in hypertensive patients and those at risk for hypertension.

It is recommended to monitor blood pressure during treatment and manage it according to clinical practices.

Zeposia Drug Interaction

Major: everolimus, pemetrexed, teriflunomide, lamivudine / zidovudine, cobimetinib, doxorubicin liposomalModerate: dextroamphetamine, fentanyl, metoprololUnknown: multivitamin with minerals, multivitamin with minerals, calcium / vitamin d, clindamycin, doravirine / lamivudine / tenofovir, pirfenidone, vancomycin, omega-3 polyunsaturated fatty acids, immune globulin intravenous, immune globulin intravenous, emicizumab

Zeposia Disease Interaction

Major: CV diseaseModerate: CV risks, hypertension, infections, liver dysfunction, respiratory toxicity, vaccinations, encephalopathy, macular edema, MS

Volume of Distribution

The average volume of distribution of ozanimod is 5590L. Another reference mentions a volume of distribution ranging from 73-101 L/kg. This drug crosses the blood-brain barrier.

Elimination Route

Zeposia is absorbed in the gastrointestinal tract after oral administration. The Cmax of ozanimod is 0.244 ng/mL and is achieved at 6 to 8 hours after administration, reaching steady-state at about 102 hours after administration. The AUC is 4.46 ng*h/mL. Its delayed absorption reduces effects that may occur after the first dose, such as heart rate changes. The peak plasma concentration of ozanimod is low due to a high volume of distribution.

Half Life

The half-life of ozanimod ranges from 17-21 hours.

Clearance

The mean apparent oral clearance of ozanimod, according to prescribing information, is 192 L/h. Another reference indicates an oral clearance of 233 L/h.

Elimination Route

The kidneys are not a major source of elimination for ozanimod. After a 0.92 mg dose of radiolabeled ozanimod was administered, about 26% of the labeled drug was accounted for in the urine and 37 % in the feces, mainly in the form of inactive metabolites.

Innovators Monograph

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