Edaravone

Identification

Summary

Edaravone is a free radical scavenger used to delay the progression of ALS.

Brand Names

Radicava

Generic Name

Edaravone

DrugBank Accession Number

DB12243

Background

Edaravone is a free radical scavenger and neuroprotective agent with antioxidant properties.⁵ It has three tautomers.³ Edaravone works to scavenge reactive oxygen species, which have been implicated in neurological disorders, such as amyotrophic lateral sclerosis (ALS) and cerebral ischemia.^3,11,5

The intravenous formulation of edaravone was first approved in Japan in 2001 for the treatment of acute ischemic stroke.¹¹ It was later approved for the treatment of amyotrophic lateral sclerosis (ALS) in Japan and South Korea in 2015, followed by the FDA approval in May 2017 ⁶ and Health Canada approval in October 2018.¹¹ The oral suspension formulation of edaravone was approved by the FDA in May 2022 and by Health Canada in November 2022.¹³

Edaravone was initially granted orphan designation by the European Medicines Agency on June 19, 2015 ¹¹ and was under regulatory review in Europe. However, the drug manufacturer, Mitsubishi Tanabe Pharma, withdrew the Marketing Authorization Application (MAA) for edaravone from the European market on May 24, 2019, in response to the request made by the Committee for Medicinal Products for Human Use (CHMP) for a long-term study demonstrating the long-term efficacy and safety of edaravone.^10,12 Edaravone was also investigated in other disorders, such as Alzheimer's disease,¹ neuropathic pain, and ischemia-induced nerve injury.²

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Edaravone (DB12243)

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Weight

Average: 174.203
Monoisotopic: 174.07931295

Chemical Formula

C₁₀H₁₀N₂O

Synonyms

• 1-phenyl-3-methyl-5-oxo-2-pyrazoline
• 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one
• 3-methyl-1-phenyl-2-pyrazolin-5-one
• 3-methyl-1-phenyl-5-pyrazolone
• 3-methyl-1-phenylpyrazol-5-one
• Edaravone
• Methylphenylpyrazolone
• Norphenazone
• Phenyl methyl pyrazolone
• Phenylmethylpyrazolone

External IDs

• MCI-186
• NSC-12
• NSC-26139
• NSC-2629
• TW001

Pharmacology

Indication

Edaravone is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in the US and Canada.^6,7 It is also indicated to treat acute ischemic stroke in Japan.^3,4,11

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Associated Conditions

• Amyotrophic Lateral Sclerosis (ALS)

Contraindications & Blackbox Warnings

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Pharmacodynamics

Edaravone works to delay the disease progression of neurological disorders such as ischemic stroke and ALS by limiting the extent of neuronal damage or death.³

Mechanism of action

Oxidative stress and reactive oxygen species (ROS) production have been implicated in various neurological disorders, such as amyotrophic lateral sclerosis (ALS) and cerebral ischemia.^3,11,5 Oxidative stress caused by excess ROS damages endothelial cells in the cerebral vasculature as well as neuronal cell membranes, leading to neuronal cell death.³

Edaravone is a free radical scavenger that scavenges and suppresses the generation of hydroxyl radicals and peroxynitrite radicals.³ The exact mechanism of action of edaravone in ALS has not been fully elucidated; however, edaravone is thought to mediate therapeutic effects via its antioxidant properties. Since oxidative stress has been implicated in the pathophysiology of ALS and cerebral ischemia, inhibiting lipid peroxidation, suppressing endothelial cell damage induced by lipid peroxides, and scavenging free radicals may lead to neuroprotective effects.² Edaravone has no effect on superoxide production.^2,3 It is suggested that edaravone may also possess anti-inflammatory properties, as it inhibited neutrophil activation and suppressed inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) expression in animal models. It was also shown to ameliorate ROS-induced inflammatory oxidative stress after ischemic brain reperfusion.³

Absorption

One study investigated the absorption of edaravone in healthy adults, who either received a single oral (105 mg/mL) or intravenous (60 mg/60 min) dose. The mean C_max (CV%) and T_max were 1656 (44.3) ng/mL and 0.5 hours, respectively, following oral administration.⁷ The absolute oral bioavailability is about 57% because of first-pass metabolism.⁶

The mean C_max (CV%) and T_max were 1253 (18.3) ng/mL and one hour, respectively, following intravenous administration.⁷ When intravenously administered, the maximum plasma concentration (C_max) of edaravone was reached by the end of infusion.⁶

The C_max and area under the concentration-time curve (AUC) of edaravone increases more than dose-proportional over the dose range of 30 to 300 mg. Edaravone does not accumulate in plasma with once-daily or multiple-dose administration. The C_max and AUC decreased when the oral suspension formulation of edaravone was administered with a high-fat meal.⁷

Volume of distribution

After intravenous administration, edaravone has a mean volume of distribution of 63.1 L, suggesting substantial tissue distribution. Edaravone has an apparent volume of distribution of 164 L following oral administration.⁷ Edaravone readily crosses the blood-brain barrier.⁴

Protein binding

Edaravone is 92% bound to human serum proteins, mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L.⁶

Metabolism

The metabolites of edaravone have not been fully characterized. Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17). In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases. Oral edaravone results in 1.3- and 1.7-fold higher exposures for both sulfate and glucuronide metabolites, respectively, when compared to intravenously-administered edaravone because of first-pass metabolism.⁶

Route of elimination

In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate (60-80% of the dose up to 48 hours). Approximately 6-8% of the dose was recovered in the urine as the sulfate conjugate, and <1% of the dose was recovered in the urine as the unchanged drug. _In vitro_ studies suggest that the sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the kidney before excretion into the urine.⁶

Half-life

The mean terminal elimination half-life of edaravone is approximately 4.5 to nine hours. The half-lives of its metabolites range from three to six hours.⁶

Clearance

Following intravenous administration, the total clearance of edaravone is estimated to be 35.9 L/h.⁶ The apparent total clearance of edaravone is estimated to be 67.9L/h following oral administration.⁷

Adverse Effects

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Toxicity

Oral and intravenous LD₅₀ in rats are 1915 mg/kg and 631 mg/kg, respectively.⁹ There is limited information on the acute toxicity of edaravone.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Not Available

Food Interactions

• Take on an empty stomach. RADICAVA ORS should be taken in the morning on an empty stomach after overnight fasting. Food should not be consumed for 1 hour after administration except water. The higher the fat content of the previous meal, the longer the fasting time before taking RADICAVA ORS will be.

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International/Other Brands

Arone (Edinburgh Pharmaceuticals (India)) / Radicut (Mitsubishi Tanabe Pharma Corporation)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Radicava	Solution	30 mg / 100 mL	Intravenous	Mitsubishi Tanabe Pharma Corporation	2019-10-29	Not applicable
Radicava	Injection	60 mg/100mL	Intravenous	Mitsubishi Tanabe Pharma America, Inc.	2020-05-05	Not applicable
Radicava	Injection	30 mg/100mL	Intravenous	Mitsubishi Tanabe Pharma America, Inc.	2017-05-05	Not applicable
Radicava	Suspension	105 mg / 5 mL	Oral	Mitsubishi Tanabe Pharma Corporation	2023-02-09	Not applicable
Radicava Ors	Kit; Suspension	1050 mg/50mL	Oral	Mitsubishi Tanabe Pharma America, Inc.	2022-05-12	Not applicable
Radicava Ors	Kit; Suspension	735 mg/35mL	Oral	Mitsubishi Tanabe Pharma America, Inc.	2022-05-12	Not applicable

Categories

ATC Codes

N07XX14 — Edaravone

• N07XX — Other nervous system drugs
• N07X — OTHER NERVOUS SYSTEM DRUGS
• N07 — OTHER NERVOUS SYSTEM DRUGS
• N — NERVOUS SYSTEM

Drug Categories

• Antioxidants
• Central Nervous System Agents
• Compounds used in a research, industrial, or household setting
• Free Radical Scavengers
• Miscellaneous Central Nervous System Agents
• Nervous System
• Neuroprotective Agents
• OAT1/SLC22A6 Substrates
• OAT3/SLC22A8 Substrates
• Protective Agents
• Pyrazoles
• Pyrazolones
• UGT1A1 Substrates
• UGT1A6 substrate
• UGT1A9 Substrates
• UGT2B17 substrates
• UGT2B7 substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as pyrazolones. These are compounds containing a pyrazole ring which bears a ketone.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Azolines

Sub Class

Pyrazolines

Direct Parent

Pyrazolones

Alternative Parents

Benzene and substituted derivatives / Carboxylic acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds

Substituents

Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid derivative / Hydrocarbon derivative / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

ring assembly (CHEBI:31530)

Affected organisms

Not Available

Chemical Identifiers

UNII

S798V6YJRP

CAS number

89-25-8

InChI Key

QELUYTUMUWHWMC-UHFFFAOYSA-N

InChI

InChI=1S/C10H10N2O/c1-8-7-10(13)12(11-8)9-5-3-2-4-6-9/h2-6H,7H2,1H3

IUPAC Name

3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one

SMILES

CC1=NN(C(=O)C1)C1=CC=CC=C1

References

General References

1. Jiao SS, Yao XQ, Liu YH, Wang QH, Zeng F, Lu JJ, Liu J, Zhu C, Shen LL, Liu CH, Wang YR, Zeng GH, Parikh A, Chen J, Liang CR, Xiang Y, Bu XL, Deng J, Li J, Xu J, Zeng YQ, Xu X, Xu HW, Zhong JH, Zhou HD, Zhou XF, Wang YJ: Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5225-30. doi: 10.1073/pnas.1422998112. Epub 2015 Apr 6. [Article]
2. Li H, Xu K, Wang Y, Zhang H, Li T, Meng L, Gong X, Zhang H, Ou N, Ruan J: Phase I clinical study of edaravone in healthy Chinese volunteers: safety and pharmacokinetics of single or multiple intravenous infusions. Drugs R D. 2012 Jun 1;12(2):65-70. doi: 10.2165/11634290-000000000-00000. [Article]
3. Watanabe T, Tahara M, Todo S: The novel antioxidant edaravone: from bench to bedside. Cardiovasc Ther. 2008 Summer;26(2):101-14. doi: 10.1111/j.1527-3466.2008.00041.x. [Article]
4. Kikuchi K, Uchikado H, Miyagi N, Morimoto Y, Ito T, Tancharoen S, Miura N, Miyata K, Sakamoto R, Kikuchi C, Iida N, Shiomi N, Kuramoto T, Kawahara K: Beyond neurological disease: new targets for edaravone (Review). Int J Mol Med. 2011 Dec;28(6):899-906. doi: 10.3892/ijmm.2011.795. Epub 2011 Sep 15. [Article]
5. Cruz MP: Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis. P T. 2018 Jan;43(1):25-28. [Article]
6. FDA Approved Drug Products: RADICAVA (edaravone) intravenous injection and RADICAVA ORS (edaravone) oral suspension [Link]
7. Health Canada Approved Drug Products: RADICAVA (edaravone) oral suspension [Link]
8. Cayman Chemical: Edaravone MSDS [Link]
9. CymitQuimica: Edaravone MSDS [Link]
10. EMA: Radicava; Withdrawal of the marketing authorisation application [Link]
11. EMA Withdrawal assessment report: Radicava [Link]
12. The Pharma Letter: Mitsubishi Tanabe pulls Radicava MAA for ALS in the Europe [Link]
13. Newswire: MITSUBISHI TANABE PHARMA CANADA ANNOUNCES CANADIAN AUTHORIZATION OF RADICAVA® (EDARAVONE) ORAL SUSPENSION FOR THE TREATMENT OF PATIENTS WITH ALS [Link]

External Links

Human Metabolome Database

HMDB0251697

KEGG Drug

D01552

KEGG Compound

C13008

PubChem Compound

4021

PubChem Substance

347828521

ChemSpider

3881

BindingDB

50200541

RxNav

1921877

ChEBI

31530

ChEMBL

CHEMBL290916

ZINC

ZINC000018203737

PDBe Ligand

W1P

Wikipedia

Edaravone

PDB Entries

5s3i / 5s52

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Cerebral Infarctions	1
4	Completed	Treatment	Myocardial Infarction / Reperfusion Injury	1
4	Completed	Treatment	Stroke	1
3	Active Not Recruiting	Treatment	Amyotrophic Lateral Sclerosis (ALS)	2
3	Completed	Treatment	Acute Ischemic Stroke	1
3	Completed	Treatment	Acute Ischemic Stroke / Edaravone Dexborneol / Mechanical Thrombectomy / Phase III	1
3	Completed	Treatment	Amyotrophic Lateral Sclerosis (ALS)	5
3	Recruiting	Treatment	Amyotrophic Lateral Sclerosis (ALS)	2
2	Completed	Treatment	Acute Ischemic Stroke	2
2	Completed	Treatment	Brain Necrosis / Nasopharyngeal Carcinoma (NPC)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	30 mg/100mL
Injection	Intravenous	60 mg/100mL
Injection, solution, concentrate	Intravenous
Solution	Intravenous	30 mg / 100 mL
Suspension	Oral	105 mg / 5 mL
Kit; suspension	Oral	1050 mg/50mL
Kit; suspension	Oral	735 mg/35mL
Solution	Intravenous	30 mg/20mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US6933310	No	2005-08-23	2020-11-13
US11241416	No	2019-11-01	2039-11-01
US10987341	No	2021-04-27	2039-11-01
US11478450	No	2019-11-01	2039-11-01

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	129.7	https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215446s000lbl.pdf
boiling point (°C)	287	https://cdn.caymanchem.com/cdn/msds/13320m.pdf
logP	1.12	https://static.cymitquimica.com/products/04/pdf/sds-C13105000.pdf
pKa	7.0	Watanabe T, Tahara M, Todo S: The novel antioxidant edaravone: from bench to bedside. Cardiovasc Ther. 2008 Summer;26(2):101-14. doi: 10.1111/j.1527-3466.2008.00041.x. [A19140]

Predicted Properties

Property	Value	Source
Water Solubility	0.939 mg/mL	ALOGPS
logP	0.53	ALOGPS
logP	1.53	Chemaxon
logS	-2.3	ALOGPS
pKa (Strongest Acidic)	13.45	Chemaxon
pKa (Strongest Basic)	-1.5	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	32.67 Å2	Chemaxon
Rotatable Bond Count	1	Chemaxon
Refractivity	49.49 m3·mol-1	Chemaxon
Polarizability	18.61 Å3	Chemaxon
Number of Rings	2	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-004i-1900000000-9c17dd936441a10926dc

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Drug created at October 20, 2016 21:42 / Updated at August 03, 2023 15:04