Safinamide

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Safinamide
Safinamide.svg
Clinical data
Trade names Xadago, Onstryv
Other namesEMD-1195686, PNU-15774E;
(2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methylamino]propanamide
AHFS/Drugs.com Monograph
Pregnancy
category
  • Fetal malformations in animal studies [1]
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 95%
Protein binding 88–90%
Metabolism Amidases, glucuronidation
Elimination half-life 20–30 hrs
Excretion 76% Kidney, 1.5% faeces
Identifiers
  • N2-{4-[(3-fluorobenzyl)oxy]benzyl}-L-alaninamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.120.167 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H19FN2O2
Molar mass 302.349 g·mol−1
3D model (JSmol)
  • O=C(N)[C@@H](NCc2ccc(OCc1cccc(F)c1)cc2)C
  • InChI=1S/C17H19FN2O2/c1-12(17(19)21)20-10-13-5-7-16(8-6-13)22-11-14-3-2-4-15(18)9-14/h2-9,12,20H,10-11H2,1H3,(H2,19,21)/t12-/m0/s1 Yes check.svgY
  • Key:NEMGRZFTLSKBAP-LBPRGKRZSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Safinamide, sold under the brand name Xadago, is a medication used as treatment for Parkinson's disease with "off" episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B. [4] [5] [7]

Contents

It was approved in the European Union in February 2015, [4] in the United States in March 2017, [5] and in Canada in January 2019. [2]

Medical uses

Safinamide is used to treat idiopathic Parkinson's disease as add-on for people taking a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson drugs, to help with "off" episodes when levodopa stops working. [4] [5] [7]

Contraindications

Safinamide is contraindicated in people with severe liver impairment, with albinism, retinitis pigmentosa, severe diabetic neuropathy, uveitis and other disorders of the retina. Combination with other monoamine oxidase (MAO) inhibitors and pethidine is also contraindicated. [4]

It is not safe for women to take during pregnancy. [5] It is excreted in breast milk and the effects on infants are unknown. [4]

Adverse effects

Common adverse events in clinical trials (in more than 1% of people) included nausea, dizziness, tiredness, sleeplessness, orthostatic hypotension (low blood pressure), and headache. There was no significant difference in the occurrence of these effects between safinamide and placebo. [8] [9]

Overdose

Expected overdose effects are hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia. In studies, a single person was suspected to have overdosed for a month; symptoms were confusion, drowsiness and mydriasis (dilation of the pupils) and subsided completely after the drug was discontinued. No specific antidote is available. [8]

Interactions

As a MAO inhibitor, safinamide can theoretically cause hypertensive crises, serotonin syndrome and other severe side effects when combined with other MAO inhibitors or with drugs that are known to interact with MAO inhibitors, such as pethidine, dextromethorphan, selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants. An interaction with tyramine, a substance found in various foods, could be expected by the same reasoning but has been excluded in studies. [8]

Another theoretical interaction is with drugs with affinity to the transporter protein ABCG2 (also known as BCRP), such as pitavastatin, pravastatin, ciprofloxacin, methotrexate, and diclofenac; a study with the latter has shown no clinical relevance. [10] A study testing possible interactions with amidase inhibitors is part of the post-authorisation development plan. [1] There are no relevant interactions related to cytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated by CYP3A4. [8]

Pharmacology

Mechanisms of action

Like the older antiparkinson drugs selegiline and rasagiline, safinamide is a selective monoamine oxidase B inhibitor, reducing degradation of dopamine; in contrast to the other two, its action is reversible. Safinamide also inhibits glutamate release [9] [11] and dopamine and serotonin reuptake. [12] It binds to the sigma receptors as well, with IC50 values for binding inhibition of 19 nM for σ1 and 1,590 nM for σ2. [13] Additionally, it blocks sodium and calcium channels, [11] [14] the relevance of which for its antiparkinson action is however unknown. [8]

Pharmacokinetics

Safinamide is absorbed quickly and nearly completely from the gut and reaches highest blood plasma concentrations after 1.8 to 2.8 hours. There is no relevant first-pass metabolism; total bioavailability is 95%. The substance is bound to plasma proteins to 88–90%. [8]

The metabolism is not well understood. The principal step is mediated by amidases which have not been identified, and produces safinamide acid (NW-1153). Other relevant metabolites are O-debenzylated safinamide (NW-1199), [10] the N-dealkylated amine which is then oxidized to a carboxylic acid (NW-1689), and the glucuronide of the latter. [8] [15] In tests with liver microsomes, dealkylation seemed to be mediated by CYP3A4, but other CYP enzymes appear to be involved as well. Safinamide acid binds to the organic anion transporter 3 (OAT3), but this has probably no clinical relevance. Safinamide itself transiently binds to ABCG2. No other transporter affinities have been found in preliminary studies. [8]

Safinamide is eliminated, mainly (>90%) in form of its metabolites, via the kidney, with an elimination half-life of 20 to 30 hours. Only 1.5% are found in the stool. [8]

Metabolism pathways of safinamide. Enzymes: CYP = cytochrome P450, MAO-A = monoamine oxidase A, ALDH = aldehyde dehydrogenases, UGT = UDP-glucuronosyltransferases. Gluc = acyl glucuronide. Safinamide metabolism.svg
Metabolism pathways of safinamide. Enzymes: CYP = cytochrome P450, MAO-A = monoamine oxidase A, ALDH = aldehyde dehydrogenases, UGT = UDP-glucuronosyltransferases. Gluc = acyl glucuronide.

History

The compound was originally discovered at Farmitalia-Carlo Erba, [16] which was acquired by Pharmacia in 1993. In 1995, Pharmacia merged with Upjohn. Safinamide was first disclosed in 1998. [17] In the course of a major restructuring in the same year, all rights for safinamide were transferred to the newly formed company Newron Pharmaceuticals, which developed the drug until it was sold to Merck KGaA in 2006. [18]

In 2007, a Phase III clinical trial was started, scheduled to run until 2011. [19] In October 2011 Merck, now Merck-Serono, announced that they would give all rights to develop the compound back to Newron because they wanted to prioritise other projects and had corrected their estimates for safinamide's market potential downwards. [20]

The US Food and Drug Administration (FDA) refused to file Newron's application in 2014 on formal grounds. [21] Newron re-applied in December 2014. [22] In spring 2015, following a commercial agreement between Newron and the Italian pharmaceutical company Zambon, the European Medicines Agency (EMA) approved the drug. [23] In the following years, the drug has been launched in several European countries. [24] Safinamide is the first antiparkinson medication to be approved for ten years. [25] Safinamide was approved by US FDA in March 2017 for people with Parkinsons taking levodopa/carbidopa during "off" episodes. [26] [27]

Research

Potential additional uses might be restless legs syndrome (RLS) and epilepsy. [28] Safinamide was being tested in Phase II trials in 2008, but no results are available. When used as an adjunct to parkinsonian medication, safinamide was found to be efficacious in reducing pain in PD. [29]

In experiments with rats (but not in those with monkeys), retinopathies have been observed. [1] [25]

Related Research Articles

<span class="mw-page-title-main">Monoamine oxidase inhibitor</span> Type of medication

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Tranylcypromine</span> Irreversible non-selective MAO inhibitor Antidepressant drug

Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively. It is also effective in the treatment of ADHD.

<span class="mw-page-title-main">Selegiline</span> Monoamine oxidase inhibitor

Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and used off-label for a variety of other indications, but has not been formally approved for any other use. The medication, in the form licensed for depression, has modest effectiveness for this condition that is similar to that of other antidepressants. Selegiline is provided as a swallowed tablet or capsule or an orally disintegrating tablet (ODT) for Parkinson's disease and as a patch applied to skin for depression.

<span class="mw-page-title-main">Cabergoline</span> Chemical compound

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Tetrabenazine</span> Medication for hyperkinetic movement disorders

Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s.

<span class="mw-page-title-main">Isocarboxazid</span> Antidepressant

Isocarboxazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant. Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.

<span class="mw-page-title-main">Tolcapone</span> Chemical compound

Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.

<span class="mw-page-title-main">Neuromodulation</span> Regulation of neurons by neurotransmitters

Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfiguring synaptic connectivity.

<span class="mw-page-title-main">Rasagiline</span> Chemical compound

Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The drug is taken by mouth.

<span class="mw-page-title-main">Pargyline</span> Chemical compound

Pargyline, sold under the brand name Eutonyl among others, is a monoamine oxidase inhibitor (MAOI) medication which has been used to treat hypertension but is no longer marketed. It has also been studied as an antidepressant, but was never licensed for use in the treatment of depression. The drug is taken by mouth.

Catechol-<i>O</i>-methyltransferase inhibitor Medication

A catechol-O-methyltransferase inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

<span class="mw-page-title-main">Benzofuranylpropylaminopentane</span> Chemical compound

(–)-Benzofuranylpropylaminopentane is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active in animals.

<span class="mw-page-title-main">Monoamine oxidase B</span> Protein-coding gene in the species Homo sapiens

Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the MAOB gene.

<span class="mw-page-title-main">Levodopa</span> Dopaminergic medication

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.

<span class="mw-page-title-main">Carbidopa/levodopa/entacapone</span> Anti Parkinson medicine

Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.

<span class="mw-page-title-main">Plasma membrane monoamine transporter</span> Protein-coding gene in the species Homo sapiens

The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 and has been identified as a potential alternate target for treating various conditions.

<span class="mw-page-title-main">Opicapone</span> Chemical compound

Opicapone, sold under the brand name Ongentys, is a medication which is administered together with levodopa in people with Parkinson's disease. Opicapone is a catechol-O-methyltransferase (COMT) inhibitor.

(<i>R</i>)-1-Aminoindane Major metabolite of rasagiline

(R)-1-Aminoindane ((R)-1-AI; developmental code name TVP-136 or TV-136), or (R)-1-aminoindan, is the major metabolite of the selective MAO-B inhibitor and antiparkinsonian agent rasagiline ((R)-N-propargyl-1-aminoindane). In contrast to rasagiline, it lacks significant monoamine oxidase inhibition. In addition, unlike selegiline and its amphetamine metabolites, it lacks monoamine reuptake-inhibiting and -releasing activities and associated amphetamine-like psychostimulant effects. However, (R)-1-aminoindane retains neuroprotective effects and certain other activities.

References

  1. 1 2 3 "Summary of the risk management plan (RMP) for Xadago (safinamide)" (PDF). European Medicines Agency. January 2015. Archived from the original (PDF) on 29 March 2017. Retrieved 29 September 2016.
  2. 1 2 "Onstryv Product information". Health Canada. 25 April 2012. Retrieved 21 July 2019.
  3. ↑ "Summary Basis of Decision (SBD) for Onstryv". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  4. 1 2 3 4 5 6 "Xadago - Summary of Product Characteristics". UK Electronic Medicines Compendium. 1 February 2017. Retrieved 2 April 2017.
  5. 1 2 3 4 5 "Safinimide label" (PDF). FDA. March 2017. Retrieved 2 April 2017. See FDA index page for NDA 207145 for updates.
  6. ↑ "Xadago EPAR". European Medicines Agency (EMA). 24 February 2015. Retrieved 27 August 2024.
  7. 1 2 Perez-Lloret S, Rascol O (2016). "The safety and efficacy of safinamide mesylate for the treatment of Parkinson's disease". Expert Review of Neurotherapeutics. 16 (3): 245–258. doi:10.1586/14737175.2016.1150783. hdl: 11336/41809 . PMID   26849427. S2CID   37787896.
  8. 1 2 3 4 5 6 7 8 9 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  9. 1 2 Spreitzer H (14 April 2014). "Neue Wirkstoffe – Safinamid". Österreichische Apothekerzeitung (in German) (8/2014): 30.
  10. 1 2 3 "Summary of Product Characteristics for Xadago" (PDF). European Medicines Agency. 24 February 2015. Archived from the original (PDF) on 17 March 2018. Retrieved 23 September 2016.
  11. 1 2 Caccia C, Maj R, Calabresi M, Maestroni S, Faravelli L, Curatolo L, et al. (October 2006). "Safinamide: from molecular targets to a new anti-Parkinson drug". Neurology. 67 (7 Suppl 2): S18–S23. doi:10.1212/wnl.67.7_suppl_2.s18. PMID   17030736. S2CID   26420481.{{cite journal}}: CS1 maint: overridden setting (link)
  12. ↑ Fabbri M, Rosa MM, Abreu D, Ferreira JJ (December 2015). "Clinical pharmacology review of safinamide for the treatment of Parkinson's disease". Neurodegenerative Disease Management. 5 (6): 481–496. doi:10.2217/nmt.15.46. PMID   26587996.
  13. ↑ Salvati P, Maj R, Caccia C, Cervini MA, Fornaretto MG, Lamberti E, et al. (March 1999). "Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound". The Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1151–1159. PMID   10027853.{{cite journal}}: CS1 maint: overridden setting (link)
  14. ↑ Pevarello P, Bonsignori A, Caccia C, Amici R, McArthur RA, Fariello RG, et al. (September 1999). "Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants". Bioorganic & Medicinal Chemistry Letters. 9 (17): 2521–2524. doi:10.1016/s0960-894x(99)00415-1. PMID   10498200.{{cite journal}}: CS1 maint: overridden setting (link)
  15. 1 2 Krösser S, Marquet A, Gallemann D, Wolna P, Fauchoux N, Hermann R, et al. (December 2012). "Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects". Biopharmaceutics & Drug Disposition. 33 (9): 550–559. doi: 10.1002/bdd.1822 . PMID   23097240. S2CID   12986951.
  16. ↑ Pevarello P, Varasi M (2018). "Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinson's Disease". In Fischer J, Klein C, Childers WE (eds.). Successful Drug Discovery. Vol. 3. pp. 383–415. doi:10.1002/9783527808694.ch14. ISBN   9783527808694.
  17. ↑ Pevarello P, Bonsignori A, Dostert P, Heidempergher F, Pinciroli V, Colombo M, et al. (February 1998). "Synthesis and anticonvulsant activity of a new class of 2-[(arylalky)amino]alkanamide derivatives". Journal of Medicinal Chemistry. 41 (4): 579–590. doi:10.1021/jm970599m. PMID   9484507.{{cite journal}}: CS1 maint: overridden setting (link)
  18. ↑ "Wichtigste Ergebnisse der Langzeitstudie mit Safinamid als Begleittherapie zu Levodopa bei Parkinson im fortgeschrittenen Stadium" [Major results from the long-term study of safinamide as add-on to levodopa for late-stage Parkinson] (Press release) (in German). Merck KGaA. 4 November 2010. Archived from the original on 11 June 2011.
  19. ↑ "Study of Safinamide in Early Parkinson's Disease as Add-on to Dopamine Agonist (MOTION)". PDtrials.org. Archived from the original on 1 January 2011.
  20. ↑ "Merck Returns Rights for Safinamide to Newron" (Press release). Merck Group. 21 October 2011.
  21. ↑ "Information about FDA Refusal to File" (Press release). Newron. 29 July 2014. Archived from the original on 4 March 2016. Retrieved 22 September 2016.
  22. ↑ "Information about FDA re-application" (PDF) (Press release). Newron. 29 December 2014. Archived from the original (PDF) on 4 March 2016. Retrieved 22 September 2016.
  23. ↑ "Xadago EPAR Public assessment report" (PDF). European Medicines Agency. 18 December 2014.
  24. ↑ "Parkinson, Zambon annuncia l'arrivo in Italia di safinamide" [Parkinson, Zambon announces the arrival of safinamide in Italy]. Aboutpharma (in Italian). 29 February 2016.
  25. 1 2 Klement A (18 July 2016). "Xadago". Österreichische Apothekerzeitung (in German) (15/2016): 10.
  26. ↑ "FDA approves drug to treat Parkinson's disease" (Press release). Food and Drug Administration. 21 March 2017.
  27. ↑ "After an odyssey of setbacks, FDA finally green-lights Newron's Parkinson's drug Xadago". Endpoints News. 21 March 2017. Retrieved 21 March 2017.
  28. ↑ Chazot PL (July 2007). "Safinamide for the treatment of Parkinson's disease, epilepsy and restless legs syndrome". Current Opinion in Investigational Drugs. 8 (7): 570–579. PMID   17659477.
  29. ↑ Qureshi AR, Rana AQ, Malik SH, Rizvi SF, Akhter S, Vannabouathong C, et al. (2018). "Comprehensive Examination of Therapies for Pain in Parkinson's Disease: A Systematic Review and Meta-Analysis". Neuroepidemiology. 51 (3–4): 190–206. doi: 10.1159/000492221 . PMID   30153669.{{cite journal}}: CS1 maint: overridden setting (link)
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