Safinamide

Mechanism

Chemical and Commercial Profile

Common trade names: Xadago.
Group: Antiparkinsonian, selective reversible inhibitor of the enzyme monoamine oxidase type B and sodium/calcium channel modulator.

Mechanism of Action

Safinamide acts through a double complementary mechanism of action, dependent on free concentration:

1. Dopaminergic Mechanism (Selective of MAO-B): It inhibits in a reversible, selective and high affinity way the enzyme MAO-B in the glial striatum, indirectly prolonging the permanence of extracellular dopamine. It has 1000 times greater binding selectivity for MAO-B compared to MAO-A.
2. Glutamatergic Mechanism (Ion Channels): It selectively blocks voltage-gated sodium channels in their inactive state, secondarily modulating calcium entry through N/P-type channels and depressing excessive presynaptic release of glutamate. This mechanism reduces the development of peak dose dyskinesias.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and almost complete orally; 95% bioavailability. It is not delayed by the presence of food. The plasma peak is reached after 2 hours.
• Distribution: Very high binding to plasma proteins (90%). Large distribution volume of 1.8 L/kg. It quickly crosses the blood-brain barrier.
• Metabolism: Hepatic oxidative catalyzed mainly by plasma amidases and the isoenzyme CYP3A4. Generates inactive metabolites.
• Excretion: Renal (80%) mainly in the form of inactive demethylated metabolites and 10% in unchanged form.
• Half-life (t_1/2): 20 to 26 hours, ideal for a single daily administration.

Indicators and dose

Indications

• Adjuvant treatment of advanced Idiopathic Parkinson's Disease with motor fluctuations ("wearing-off"), in combination with a stable dose of levodopa/carbidopa or levodopa/benserazide.

Dosage and Settings

• Initial Dose: 50 mg once a day orally.
• Increments: After 2 weeks of good tolerance, increase to 100 mg once a day orally (maximum authorized dose).
• Liver Failure: Decrease the daily dose to 50 mg/day in compensated Child-Pugh B cirrhosis; Absolutely contraindicated in Child-Pugh C through the hepatic CYP3A4-dependent elimination pathway.
• Kidney Failure: No adjustments required in moderate to severe kidney failure.

Security

Contraindications

• Concomitant use with other monoamine oxidase inhibitors (MAOIs) or with **pethidine, tramadol or methadone** (risk of severe serotonin syndrome and hyperthermia).
• Severe decompensated liver failure (Child-Pugh C).

Adverse Effects (ADR)

• CNS: Early-onset transient dyskinesias (occurs in 10% of patients; requires reducing the dose of levodopa by 10-20% at the beginning), visual hallucinations, sleep insomnia, dizziness, headache.
• Gastrointestinal: Temporary nausea, motor constipation, abdominal pain.
• Ophthalmics: Late-onset cataracts in experimental models; Periodic ophthalmic monitoring is recommended in predisposed elderly people.

Clinical Interactions

• CYP3A4 inhibitors: Ketoconazole or voriconazole moderately increase safinamide levels, requiring monitoring of cognitive tolerance of the compound.
• Antidepressants: Risk of serotonin syndrome in combination with linezolid, tramadol, triptans, St. John's Wort and lithium.

Pregnancy and Breastfeeding

FDA Category: C. Very limited human data; associates decreased embryonic growth in animals. Breastfeeding: Absolutely contraindicated. Like other dopaminergic drugs, it potently inhibits pituitary prolactin release reflexively, suppressing lactation, in addition to being excreted in breast milk.