Opicapone

Identification

Summary

Opicapone is a catechol-O-methyltransferase inhibitor used as an adjunct treatment for Parkinson's Disease in adults currently receiving levodopa and a dopa decarboxylase inhibitor.

Brand Names

Ongentys

Generic Name

Opicapone

DrugBank Accession Number

DB11632

Background

Opicapone is a potent, reversible, and peripherally-acting third-generation inhibitor of catechol-o-methyltransferase (COMT), an enzyme involved in the breakdown of various catecholamines including dopamine.^4,5 Many patients with Parkinson’s disease treated with levodopa plus a dopa decarboxylase (DDC) inhibitor (eg carbidopa) experience motor complications over time, which calls for the management of these symptoms through the use of a dopamine agonist, a monoamine oxidase B inhibitor (selegiline, rasagiline), a catechol-O-methyl transferase (COMT) inhibitor, or amantadine, or using a modified-release formulation of levodopa.⁶

Opicapone is used for adjunct therapy to levodopa and carbidopa in adult patients with Parkinson's disease and end-of-dose motor fluctuations. Opicapone was approved for use by the European Commission in June 2016 ⁷ and the FDA in April 2020.¹³ It is marketed under the brand name Ongentys as once-daily oral capsules. Exhibiting a long duration of action that exceeds 24 hours, opicapone can be administered once-daily ⁶ and demonstrates the lowest risk for cytotoxicity compared to other catechol-O-methyltransferase inhibitors.⁵

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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Similar Structures

Structure for Opicapone (DB11632)

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Weight

Average: 413.17
Monoisotopic: 411.9977395

Chemical Formula

C₁₅H₁₀Cl₂N₄O₆

Synonyms

• Opicapona
• Opicapone

External IDs

• BIA 9-1067
• BIA-9-1067
• BIA-91067

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Pharmacology

Indication

Opicapone is indicated as adjunctive therapy in adults with Parkinson’s disease and end-of-dose motor fluctuations or “off” episodes whose symptoms cannot be stabilized on the combination therapy of levodopa and DOPA decarboxylase inhibitor (e.g., carbidopa).^10,13

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Adjunct therapy in management of	Parkinson's disease		••••••••••••	•••••	••• •• •••• ••••• •••••••••••• •••• •••••• •• ••••••••••	•••••••
Adjunct therapy in management of	Parkinson's disease (pd)		••••••••••••	•••••	••• •••••••• •• ••••••••• •••••••	•••••••

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Pharmacodynamics

Opicapone is a COMT inhibitor that serves to improve the availability and duration of action of levodopa (L-Dopa), a standard pharmacological treatment for Parkinson's Disease. Opicapone works by blocking the peripheral degradation of L-Dopa mediated by COMT.¹ Opicapone has a long duration of action: following administration of a 50 mg dose, COMT inhibition lasted for more than 24 hours.¹⁰ In clinical trials, opicapone as adjunct therapy to L-Dopa plus a dopa decarboxylase inhibitor significantly improved motor fluctuations than placebo, and the effects were comparable to entacapone.¹

Mechanism of action

Levodopa (L-Dopa) is the gold standard for managing motor and some non-motor symptoms associated with Parkinson's Disease; however, only a small fraction of administered L-Dopa actually crosses the blood-brain barrier to exert its therapeutic action and patients face the risk of developing end-of-dose motor fluctuations, which reflects the rapid peripheral metabolism of L-dopa by aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT).¹

Opicapone is a peripheral, selective, and reversible catechol-O-methyltransferase (COMT) inhibitor. It displays a high binding affinity that is in sub-picomolar ranges, resulting in a slow complex dissociation rate constant and long duration of action in vivo.¹⁰ When opicapone is added to the treatment regimen that contains L-Dopa and DOPA decarboxylase inhibitor, opicapone helps to increase the plasma levels and enhance the therapeutic efficacy of L-Dopa.¹

Target	Actions	Organism
ACatechol O-methyltransferase	inhibitor	Humans

Absorption

Orally administered opicapone demonstrates a linear, dose-dependent absorption profile.⁵ Opicapone is rapidly absorbed,² with an oral bioavailability of about 20%.¹⁰ Following administration of a single 50 mg dose of opicapone, the median T_max was two hours, ranging from one to four hours. A moderate fat or moderate calorie meal was shown to decrease the C_max by 62%, the mean overall plasma exposure (AUC) by 31%, and the Tmax by 4 hours.¹³

Volume of distribution

Following oral administration, the apparent V_d of opicapone at a dose of 50 mg was 29 L with an inter-subject variability of 36%.¹⁰ One study showed small systemic accumulation after multiple-dosing.²

Protein binding

Opicapone is >99% bound to plasma proteins, which is independent of the drug concentration.¹³

Metabolism

According to clinical and in vitro studies, sulphation is the primary metabolic pathway of opicapone, forming the inactive metabolite. Opicapone can also undergo glucuronidation, COMT-mediated methylation, reduction, and glutathione conjugation.^10,13

As two major circulating metabolites, BIA 9-1103 (3-O-sulphated opicapone) accounts for 67.1% of the total radioactivity and BIA 9-1104 (4-O-methylated opicapone) accounts for 20.5% of the total radioactivity. Other metabolites are generally unquantifiable in plasma samples.^8,10 Opicapone can undergo N-oxide reduction to form BIA 9-1079, which was shown to be an active metabolite in non-clinical studies;³ however, it is generally undetectable in humans.⁸ Other inactive metabolites include BIA 9-1100, BIA 9-1101, and BIA 9-1106.³

Hover over products below to view reaction partners

• Opicapone
  • BIA 9-1103
  • BIA 9-1104
  • BIA 9-1100
  • BIA 9-1079
  • BIA 9-1101
  • BIA 9-1106

Route of elimination

Following administration of a single 100 mg dose of radiolabeled opicapone in healthy subjects, about 70% of the total dose was recovered in feces, where 22% of the recovered dose was excreted as an unchanged parent drug. About 20% of the total dose was recovered in exhaled air and about 5% was recovered in the urine, where less than 1% of the recovered dose was in an unchanged form.¹³ The primary detectable metabolite in the urine was the glucuronide metabolite.¹⁰

Half-life

The mean elimination half-life of opicapone is one to two hours.¹³ Despite the short half-life, the observed half-life of opicapone-induced COMT inhibition in human red blood cells was 61.6 hours with a standard deviation of 37.6 hours.³

Clearance

Following oral administration of 50 mg opicapone, the apparent total body clearance was 22 L/h, with an inter-subject variability of 45%.¹⁰

Adverse Effects

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Toxicity

There is no reported LD₅₀ data of opicapone. As there is no known antidote for opicapone overdose, overdosage should be managed with symptomatic and supportive treatment. Removal of the drug through gastric lavage and/or inactivation by administering activated charcoal should be considered.^10,13

Pathways

Not Available

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Not Available

Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abaloparatide	The risk or severity of adverse effects can be increased when Abaloparatide is combined with Opicapone.
Acebutolol	The risk or severity of adverse effects can be increased when Acebutolol is combined with Opicapone.
Aldesleukin	The risk or severity of adverse effects can be increased when Aldesleukin is combined with Opicapone.
Aliskiren	The risk or severity of adverse effects can be increased when Aliskiren is combined with Opicapone.
Ambrisentan	Opicapone may increase the hypotensive activities of Ambrisentan.

Food Interactions

• Take separate from meals. Take opicapone at least one hour before or after eating, as a moderate calorie meal decreases Cmax and overall plasma exposure to the drug, and delays Tmax.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Ongentys	Capsule	50 mg	Oral	Bial Portela Cª, s.a.	2016-09-08	Not applicable
Ongentys	Capsule	25 mg/1	Oral	Neurocrine Biosciences, Inc.	2020-04-24	Not applicable
Ongentys	Capsule	25 mg	Oral	Bial Portela Cª, s.a.	2016-09-08	Not applicable
Ongentys	Capsule	50 mg	Oral	Bial Portela Cª, s.a.	2016-09-08	Not applicable
Ongentys	Capsule	50 mg	Oral	Bial Portela Cª, s.a.	2016-09-08	Not applicable

Categories

ATC Codes

N04BX04 — Opicapone

• N04BX — Other dopaminergic agents
• N04B — DOPAMINERGIC AGENTS
• N04 — ANTI-PARKINSON DRUGS
• N — NERVOUS SYSTEM

Drug Categories

• Anti-Dyskinesia Agents
• Anti-Parkinson Drugs
• BCRP/ABCG2 Substrates
• Central Nervous System Agents
• COMT Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP1A2 Inhibitors (weak)
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2B6 Inhibitors (weak)
• Cytochrome P-450 CYP2C19 Inducers
• Cytochrome P-450 CYP2C19 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors (weak)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Dopamine Agents
• Enzyme Inhibitors
• Hypotensive Agents
• Nervous System
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 substrates
• OATP2B1/SLCO2B1 substrates
• Oxazoles
• P-glycoprotein substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as phenyloxadiazoles. These are polycyclic aromatic compounds containing a benzene ring linked to a 1,2,4-oxadiazole ring through a CC or CN bond.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Azoles

Sub Class

Oxadiazoles

Direct Parent

Phenyloxadiazoles

Alternative Parents

Nitrophenols / Nitrobenzenes / Catechols / Nitroaromatic compounds / Polyhalopyridines / 1-hydroxy-2-unsubstituted benzenoids / Methylpyridines / 1-hydroxy-4-unsubstituted benzenoids / 2-halopyridines / Aryl chlorides / Pyridinium derivatives / Heteroaromatic compounds / Oxacyclic compounds / Azacyclic compounds / Organic oxoazanium compounds / Organonitrogen compounds / Organic salts / Organooxygen compounds / Organochlorides / Hydrocarbon derivatives / Organic oxides / Organic cations

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Substituents

1-hydroxy-2-unsubstituted benzenoid / 1-hydroxy-4-unsubstituted benzenoid / 2-halopyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / C-nitro compound / Catechol / Heteroaromatic compound / Hydrocarbon derivative / Methylpyridine / Monocyclic benzene moiety / Nitroaromatic compound / Nitrobenzene / Nitrophenol / Organic cation / Organic nitro compound / Organic nitrogen compound / Organic oxide / Organic oxoazanium / Organic oxygen compound / Organic salt / Organochloride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Oxacycle / Phenol / Phenyl-1,2,4-oxadiazole / Polyhalopyridine / Pyridine / Pyridinium

show 24 more

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

Y5929UIJ5N

CAS number

923287-50-7

InChI Key

ASOADIZOVZTJSR-UHFFFAOYSA-N

InChI

InChI=1S/C15H10Cl2N4O6/c1-5-10(13(17)20(24)6(2)11(5)16)14-18-15(27-19-14)7-3-8(21(25)26)12(23)9(22)4-7/h3-4,22-23H,1-2H3

IUPAC Name

2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl]-4,6-dimethylpyridin-1-ium-1-olate

SMILES

CC1=C(C2=NOC(=N2)C2=CC(=C(O)C(O)=C2)[N+]([O-])=O)C(Cl)=[N+]([O-])C(C)=C1Cl

References

General References

1. Scott LJ: Opicapone: A Review in Parkinson's Disease. Drugs. 2016 Sep;76(13):1293-1300. doi: 10.1007/s40265-016-0623-y. [Article]
2. Goncalves D, Alves G, Fortuna A, Soares-da-Silva P, Falcao A: Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after single and multiple oral administration: A comparative study in the rat. Toxicol Appl Pharmacol. 2017 May 15;323:9-15. doi: 10.1016/j.taap.2017.03.013. Epub 2017 Mar 16. [Article]
3. Almeida L, Rocha JF, Falcao A, Palma PN, Loureiro AI, Pinto R, Bonifacio MJ, Wright LC, Nunes T, Soares-da-Silva P: Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. Clin Pharmacokinet. 2013 Feb;52(2):139-51. doi: 10.1007/s40262-012-0024-7. [Article]
4. Bonifacio MJ, Palma PN, Almeida L, Soares-da-Silva P: Catechol-O-methyltransferase and its inhibitors in Parkinson's disease. CNS Drug Rev. 2007 Fall;13(3):352-79. doi: 10.1111/j.1527-3458.2007.00020.x. [Article]
5. Svetel M, Tomic A, Kresojevic N, Kostic V: Pharmacokinetic drug evaluation of opicapone for the treatment of Parkinson's disease. Expert Opin Drug Metab Toxicol. 2018 Mar;14(3):353-360. doi: 10.1080/17425255.2018.1430138. Epub 2018 Jan 24. [Article]
6. Opicapone:once-daily adjunctive therapy for Parkinson’s disease [Link]
7. Clinical pharmacology review of opicapone for the treatment of Parkinson's disease [Link]
8. EMA assessment report [Link]
9. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects [Link]
10. Summary of Product Characteristics: Ongentys (opicapone) oral capsules [Link]
11. Pharmacological Profile of Opicapone, a Third Generation Nitrocatechol COMT Inhibitor, in the Rat [Link]
12. Wikigenes [Link]
13. FDA Approved Drug Products: ONGENTYS (opicapone) capsules, for oral use [Link]

External Links

ChemSpider

24667564

BindingDB

50019329

RxNav

2362167

ChEBI

134699

ChEMBL

CHEMBL1089318

ZINC

ZINC000034602275

PDBe Ligand

DNI

Wikipedia

Opicapone

PDB Entries

7xgi / 7xjb

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Parkinson's Disease (PD)	2
4	Completed	Treatment	Parkinson's Disease (PD)	1
4	Completed	Treatment	Parkinson's Disease With Wearing-off Motor Fluctuations	1
4	Recruiting	Treatment	Parkinson's Disease (PD)	1
3	Active Not Recruiting	Treatment	Parkinson's Disease (PD)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	25 mg/1
Capsule	Oral	25 MG
Capsule	Oral	50 MG
Capsule	Oral	50 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9550759	No	2017-01-24	2026-07-26
US9745290	No	2017-08-29	2027-10-10
US9630955	No	2017-04-25	2032-12-12
US10583130	No	2020-03-10	2030-03-31
US8524746	No	2013-09-03	2029-07-14
US8168793	No	2012-05-01	2029-04-02
US10357468	No	2019-07-23	2035-05-27
US10071085	No	2018-09-11	2030-03-31
US8907099	No	2014-12-09	2027-05-12

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	minimal	http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002790/WC500209538.pdf

Predicted Properties

Property	Value	Source
logP	3.05	Chemaxon
pKa (Strongest Acidic)	6.12	Chemaxon
pKa (Strongest Basic)	-0.47	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	7	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	149.46 Å2	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	118.12 m3·mol-1	Chemaxon
Polarizability	37.42 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-0059-0539000000-7474afd576b5551b7ce4
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	189.81471	predicted	DeepCCS 1.0 (2019)
[M+H]+	191.95326	predicted	DeepCCS 1.0 (2019)
[M+Na]+	197.8658	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Details1. Catechol O-methyltransferase

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

O-methyltransferase activity

Specific Function

Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOP...

Gene Name

COMT

Uniprot ID

P21964

Uniprot Name

Catechol O-methyltransferase

Molecular Weight

30036.77 Da

References

1. Scott LJ: Opicapone: A Review in Parkinson's Disease. Drugs. 2016 Sep;76(13):1293-1300. doi: 10.1007/s40265-016-0623-y. [Article]
2. Tardy B, Lecompte T, Boelhen F, Tardy-Poncet B, Elalamy I, Morange P, Gruel Y, Wolf M, Francois D, Racadot E, Camarasa P, Blouch MT, Nguyen F, Doubine S, Dutrillaux F, Alhenc-Gelas M, Martin-Toutain I, Bauters A, Ffrench P, de Maistre E, Grunebaum L, Mouton C, Huisse MG, Gouault-Heilmann M, Lucke V: Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood. 2006 Sep 1;108(5):1492-6. Epub 2006 May 11. [Article]
3. EMA assessment report [Link]
4. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects [Link]
5. Summary of Product Characteristics: Ongentys (opicapone) oral capsules [Link]

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Drug created at October 17, 2016 21:26 / Updated at February 21, 2021 18:53