Chemistry:Edaravone

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Short description: Chemical compound
Edaravone
Edaravone Structural Formula V1.svg
Edaravone ball-and-stick model.png
Clinical data
Trade namesRadicava, others
Other namesMCI-186
AHFS/Drugs.comMonograph
MedlinePlusa617027
License data
Pregnancy
category
Routes of
administration		Intravenous, by mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC10H10N2O
Molar mass174.203 g·mol−1
3D model (JSmol)
  (verify)

Edaravone, sold under the brand name Radicava among others, is a medication used to treat stroke and amyotrophic lateral sclerosis (ALS).[4][5] It is given by intravenous infusion[4] and by mouth.[4][6]

The most common side effects include bruising (contusions), problems walking (gait disturbances), and headaches.[6]

The mechanism by which edaravone might be effective is unknown.[4] The medication is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS.[7]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[8]

Medical uses

Edaravone is used to help people recover from stroke in Japan,[9] and is used to treat ALS in the US and Japan.[4][7]

Adverse effects

The label carries a warning about the potential for hypersensitivity reactions to edaravone, and adverse effects include bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.[4]

The following adverse effects in at least 2% more people given the medication than were given placebo: bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.[4]

There is no data on whether it is safe for pregnant women to take, and it is unknown if edaravone is secreted in breast milk.[4]

Pharmacology

The mechanism by which edaravone might be effective in ALS is unknown.[4] The medication is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS.[7]

The half-life of edaravone is 4.5 to 6 hours and the half-lives of its metabolites are 2 to 3 hours. It is metabolized to a sulfate conjugate and a glucuronide conjugate, neither of which are active. It is primarily excreted in urine as the glucuronide conjugate form.[4]

History

Researchers first developed the free radical scavenger edaravone in late 1980s as a treatment for stroke. The approach, introduced by Koji Abe, now at Okayama University Hospital in Japan, aimed to prevent the swelling of the brain which may occur after a stroke.[10]

It has been marketed in Japan by Mitsubishi Pharma for stroke since 2001 and is now generic.[9][11]

Mitsubishi Tanabe started a phase III clinical trial in ALS in 2011, in Japan, and by June 2015, it had been approved for that use in Japan. The company had received Orphan Drug Designation for edaravone from the FDA and EU by 2016.[12]

It was approved for ALS in the US in 2017, based on a small randomized controlled clinical trial with people who had early-stage ALS in Japan, who were administered the medication for 6 months; it had failed two earlier trials in people with all stages of ALS.[4][7]

In May 2017, I.V. edaravone was approved by the FDA to treat people with amyotrophic lateral sclerosis (ALS) in the United States.[13] The FDA approval was conditioned on Mitsubishi Tanabe completing several additional studies to clarify the risks of cancer and liver disease, among other effects of the medication.[14][15]

Formulation of edaravone by mouth called TW001 (mixture of the edaravone and SBE-HP-βCD [16]) has been under development by Treeway for ALS; as of 2015, it had successfully completed Phase I trial and had received orphan status in the US and in the European Union.[17]

An oral formulation of edaravone was approved for medical use in the United States in May 2022.[4][6][18] The effectiveness of oral edaravone is based on a study that showed comparable levels of oral edaravone in the bloodstream to the levels from the IV formulation of edaravone.[6] The efficacy of edaravone for the treatment of ALS was previously demonstrated in a six-month clinical trial that served as the basis for approval in 2017.[6] In that trial, 137 participants were randomized to receive edaravone or placebo. At week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving placebo.[6] An analysis of real-world data of 194 patients from 12 ALS clinics, failed to reproduce the effect.[19]

Society and culture

Economics

The price for the medication when it launched in Japan for stroke in 2001, was set by the Japanese government at 9,931 yen/ampule.[20]

When the medication launched in Japan for ALS in 2001, the price was $35,000; the price in Japan in 2017 was $5,000, the US price at launch was around $145,000.[11] In the US the medication was approved for all people with ALS but it was unclear at approval whether insurers would agree to pay for the medication for all people with ALS, or only people in the early stages of the disease.[11][21] There are three filed trials for edaravone, demonstrating it may work in less than 5% of all ALS population.

Brand names

Brand names include Radicut, ラジカット, Radicava, Xavron.

References

  1. ↑ 1.0 1.1 "Radicava". 24 February 2023. https://www.tga.gov.au/resources/auspmd/radicava. 
  2. ↑ "Radicava edaravone 30 mg/20 mL concentrated injection ampoule (375455)". 16 February 2023. https://www.tga.gov.au/resources/artg/375455. 
  3. ↑ "Search Page - Drug and Health Product Register". 23 October 2014. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00450. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 "Radicava- edaravone injection Radicava ORS- edaravone kit". 12 May 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ce2c1c4-2a40-485c-b7cb-96a9b85d9d11. 
  5. ↑ "Chemical reactivity and uses of 1-phenyl-3-methyl-5-pyrazolone (PMP), also known as edaravone". Bioorganic & Medicinal Chemistry 28 (10): 115463. May 2020. doi:10.1016/j.bmc.2020.115463. PMID 32241621. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "FDA Approves Oral Form of ALS Treatment". 12 May 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-oral-form-treatment-adults-amyotrophic-lateral-sclerosis-als.  This article incorporates text from this source, which is in the public domain.
  7. ↑ 7.0 7.1 7.2 7.3 "ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?". Front Aging Neurosci 9: 68. 2017. doi:10.3389/fnagi.2017.00068. PMID 28382000. 
  8. ↑ (PDF) New Drug Therapy Approvals 2017 (Report). January 2018. https://www.fda.gov/media/110526/download. Retrieved 16 September 2020. 
  9. ↑ 9.0 9.1 "Effect of edaravone on favorable outcome in patients with acute cerebral large vessel occlusion: subanalysis of RESCUE-Japan Registry". Neurol. Med. Chir. (Tokyo) 55 (3): 241–7. 2015. doi:10.2176/nmc.ra.2014-0219. PMID 25739433. 
  10. ↑ "FDA Approves Edaravone as a Treatment for ALS". http://www.alsresearchforum.org/fda-approves-edaravone-as-a-treatment-for-als-2/?platform=hootsuite. 
  11. ↑ 11.0 11.1 11.2 Herper, Matthew. "The First ALS Drug In 22 Years Is Approved -- And It Costs 4 Times What It Does In Japan". Forbes. https://www.forbes.com/sites/matthewherper/2017/05/05/fda-approves-first-new-drug-to-treat-als-in-22-years/#4cde9947fb30. 
  12. ↑ Lane, EJ (20 April 2016). "Mitsubishi Tanabe says ALS drug meets PhIII endpoint". FiercePharma. http://www.fiercepharma.com/pharma-asia/mitsubishi-tanabe-says-als-drug-meets-phiii-endpoint. 
  13. ↑ "FDA approves drug to treat ALS". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 8 May 2017. Retrieved 7 May 2017.
  14. ↑ "NDA 209176 Approval letter". U.S. Food and Drug Administration (FDA). 5 May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/209176Orig1s000ltr.pdf. 
  15. ↑ "Radicava (edaravone) Injection". 20 June 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209176Orig1s000TOC.cfm. 
  16. ↑ "Hydroxypropyl-sulfobutyl-β-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes". J Pharm Sci 103 (2): 730–42. February 2014. doi:10.1002/jps.23807. PMID 24311389. 
  17. ↑ "Edaravone oral". AdisInsight. http://adisinsight.springer.com/drugs/800043880. 
  18. ↑ NDA Approval fda.gov
  19. ↑ Witzel S, Maier A, Steinbach R, et al. Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022;79(2):121–130. doi:10.1001/jamaneurol.2021.4893
  20. ↑ "Launching of Radicut Injection. 30 mg" (Press release). Mitsubishi-Tokyo Pharmaceuticals via Evaluate. 23 May 2001. Archived from the original on 3 July 2022. Retrieved 9 May 2017.
  21. ↑ Grady, Denise (5 May 2017). "A Second Drug Is Approved to Treat A.L.S.". The New York Times. https://www.nytimes.com/2017/05/05/health/fda-approves-lou-gehrigs-disease-drug.html?smid=tw-nythealth&smtyp=cur. 

Further reading

  • "Edaravone for the treatment of amyotrophic lateral sclerosis". Expert Rev Neurother 19 (3): 185–193. March 2019. doi:10.1080/14737175.2019.1581610. PMID 30810406. 
  • Pharmacoeconomic Review Report: Edaravone (Radicava): (Mitsubishi Tanabe Pharma Corporation). CADTH Common Drug Reviews. April 2019. NBK542526. 



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