Safinamide is used to treatidiopathic Parkinson's disease as add-on for people taking a stable dose oflevodopa (L-dopa) alone or in combination with other Parkinson drugs, to help with"off" episodes when levodopa stops working.[5][6][8]
Common adverse events in clinical trials (in more than 1% of people) includednausea, dizziness, tiredness, sleeplessness,orthostatic hypotension (low blood pressure), and headache. There was no significant difference in the occurrence of these effects between safinamide andplacebo.[9][10]
Expected overdose effects arehypertension (high blood pressure), orthostatic hypotension, hallucinations,psychomotor agitation, nausea, vomiting, anddyskinesia. In studies, a single person was suspected to have overdosed for a month; symptoms were confusion, drowsiness andmydriasis (dilation of the pupils) and subsided completely after the drug was discontinued. No specific antidote is available.[9]
Another theoretical interaction is with drugs with affinity to the transporter proteinABCG2 (also known as BCRP), such aspitavastatin,pravastatin,ciprofloxacin,methotrexate, anddiclofenac; a study with the latter has shown no clinical relevance.[11] A study testing possible interactions withamidase inhibitors is part of the post-authorisation development plan.[1] There are no relevant interactions related tocytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated byCYP3A4.[9]
Themetabolism 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),[11] the N-dealkylated amine which is then oxidized to acarboxylic acid (NW-1689), and theglucuronide of the latter.[9][16] In tests with livermicrosomes, dealkylation seemed to be mediated by CYP3A4, but other CYP enzymes appear to be involved as well. Safinamide acid binds to theorganic 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.[9]
Safinamide is eliminated, mainly (>90%) in form of its metabolites, via the kidney, with anelimination half-life of 20 to 30 hours. Only 1.5% are found in the stool.[9]
The compound was originally discovered atFarmitalia-Carlo Erba,[17] which was acquired byPharmacia in 1993. In 1995, Pharmacia merged withUpjohn. Safinamide was first disclosed in 1998.[18] In the course of a major restructuring in the same year, all rights for safinamide were transferred to the newly formed companyNewron Pharmaceuticals, which developed the drug until it was sold toMerck KGaA in 2006.[19]
In 2007, aPhase III clinical trial was started, scheduled to run until 2011.[20] In October 2011 Merck, nowMerck-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.[21]
The USFood and Drug Administration (FDA) refused to file Newron's application in 2014 on formal grounds.[22] Newron re-applied in December 2014.[23] In spring 2015, following a commercial agreement between Newron and the Italian pharmaceutical companyZambon, theEuropean Medicines Agency (EMA) approved the drug.[24] In the following years, the drug has been launched in several European countries.[25] Safinamide is the first antiparkinson medication to be approved for ten years.[26] Safinamide was approved by US FDA in March 2017 for people with Parkinsons taking levodopa/carbidopa during"off" episodes.[27][28]
Potential additional uses might be restless legs syndrome (RLS) andepilepsy.[29] 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.[30]
In experiments with rats (but not in those with monkeys),retinopathies have been observed.[1][26]
^abCaccia 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.PMID17030736.S2CID26420481.{{cite journal}}: CS1 maint: overridden setting (link)
^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.PMID26587996.
^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.doi:10.1016/S0022-3565(24)38068-1.PMID10027853.{{cite journal}}: CS1 maint: overridden setting (link)
^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.PMID10498200.{{cite journal}}: CS1 maint: overridden setting (link)
^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.ISBN9783527808694.
^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.PMID9484507.{{cite journal}}: CS1 maint: overridden setting (link)
^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.PMID17659477.
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