Drug information of Siponimod

Siponimod

Drug group:

Siponimod (also known as BAF312 or Mayzent) is a tablet being developed for secondary progressive MS by Novartis Pharmaceuticals. It was licensed by the European Medicines Agency (EMA) on Monday 20 January 2020.

Mechanism of effect

Sphingosine-1-phosphate (S1P) receptor modulator

Binds with high affinity to S1P receptors 1 and 5; blocks lymphocyte egress from lymph nodes, reducing the number of lymphocytes in peripheral blood

Mechanism by which siponimod exerts therapeutic effects in MS is unknown, but may involve reduction of lymphocyte migration into the central nervous system

Pharmacodynamic

Siponimod works in a similar way to the licensed treatment fingolimod.

It traps certain types of immune cell (called B and T cells) in the body's lymph nodes. This stops them from getting into the brain and spinal cord, where they could cause damage to the protective myelin coating around the nerves.

Pharmacokinetics

Absorption

Peak plasma time: 4 hr

Peak plasma concentration: 30.4 ng/mL (2 mg/day over 10 days)

AUC: 558 ng·hr/mL (2mg/day over 10 days)

Steady-state reached after ~ 6 days

Oral bioavailability: ~84%

Siponimod absorption is extensive (≥70%)

Distribution

Vd: 124 L

Animal studies show that siponimod readily crosses the blood-brain barrier

Protein bound: >99.9%

Metabolism

Extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%)

Pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and safety of siponimod in humans

Elimination

Clearance: 3.11 L/hr

Half-life: ~30 hr

Eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion; unchanged siponimod was not detected in urine

 

Drug indications

Siponimod was studied for the treatment of secondary progressive multiple sclerosis (SPMS), which is the progressive neurological decline of multiple sclerosis that happens independent of acute relapses. In active SPMS, siponimod decreases the risk of disability and MS relapses.

Dosage

  • Initiate with a 5-day titration
  • Maintenance dose (Day 6): 2 mg PO qDay

Drug contraindications

lefamulin

lefamulin will increase the level or effect of siponimod by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Lefamulin is contraindicated with CYP3A substrates know to prolong the QT interval

 

Side effects

  • Side effects reported in the phase 2 study included headache, slowing of heart rate, dizziness and nose and throat infections. In the EXPAND study side effects ranged from runny noses, to more serious conditions, like high blood pressure and low white blood cell count.

Alerts

Macular edema reported; majority of cases occurred within the first 4 months of therapy

Dose-dependent reductions in absolute FEV1 observed as early as 3 months after treatment initiation

Elevated transaminases may occur; exercise caution when treating patients with a history of significant liver disease

Incidence of hypertension reported in clinical trials in patients treated with siponimod was slightly higher than those treated with placebo; monitor blood pressure during treatment and manage appropriately

Based on animal studies, fetal harm may occur (see Pregnancy)

Rare cases of posterior reversible encephalopathy syndrome reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator; such events have not been reported for siponimod-treated patients in the development program

Severe disease exacerbation, including disease rebound, rarely reported after discontinuing S1P receptor modulator

After discontinuing, siponimod remains in the blood for up to 10 days; starting other therapies during this interval results in concomitant exposure to siponimod

May cause a decline in pulmonary function; assess pulmonary function (eg, spirometry) if clinically indicated

Bradyarrhythmia and AV conduction delays

  • Since initiation of treatment results in a transient decrease in HR and AV conduction delays, use an up-titration scheme to reach maintenance dosage
  • After first titration dose, decrease in HR starts within 1 hr, and on Day 1 declines at ~3-4 hr; with continued up-titration, further HR decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6; with continued dosing, HR starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation
  • The resting heart rate under stable dose of beta-blocker should be considered before introducing therapy

 

Pregnancy level

There are no adequate data on the developmental risk associated with the use in pregnant women

Breast feeding warning

Unknown if distributed in human breast milk


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