Identification

Name
Opicapone
Accession Number
DB11632
Type
Small Molecule
Groups
Approved, Investigational
Description

Opicapone, an investigational drug in the U.S., is a once-daily, peripherally-acting, highly-selective catechol-o-methyltransferase (COMT) inhibitor being developed as an adjunct therapy to preparations of levodopa/DOPA decarboxylase inhibitors for adult patients with Parkinson's disease and motor fluctuations [4].

In June 2016, the European Commission granted a marketing authorization valid throughout the European Union for OPC, indicated as adjunctive of levodopa decarboxylase inhibitors in adult patients suffering from Parkinson's disease and end-of-dose motor fluctuations [7].

With its convenient once-daily regimen, orally administered opicapone is an emerging COMT inhibitor alternative for use as adjunctive therapy to L-Dopa/DDCI therapy in adults with PD and end-of dose motor fluctuations who cannot be stabilized on those combinations [1].

Almost all individuals with Parkinson’s disease whom are treated with levodopa plus a dopa decarboxylase (DDC) inhibitor (eg carbidopa) will develop motor complications in time. The initial step in the management is changing the levodopa/DDC inhibitor dosage and the use of adjunct drugs. Various options include supplementing with 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 [5].

The newest adjunctive option is opicapone. This drug is a peripherally selective reversible COMT inhibitor that offers the benefit of a duration of action exceeding 24h, allowing for once-daily administration [5]. Opicapone demonstrates the lowest risk for cytotoxicity in comparison with other catechol-O-methyltransferase inhibitors [6].

Structure
Thumb
Synonyms
Not Available
External IDs
BIA 9-1067 / BIA-9-1067 / BIA-91067
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OngentysCapsule50 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule25 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule25 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule50 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule50 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule25 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule50 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule50 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule25 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
OngentysCapsule50 mgOralBial Portela & Cª, S.A.2016-06-24Not applicableEu
Categories
UNII
Y5929UIJ5N
CAS number
923287-50-7
Weight
Average: 413.17
Monoisotopic: 411.9977395
Chemical Formula
C15H10Cl2N4O6
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

Pharmacology

Indication

Opicapone is approved as an adjunctive therapy in adults with Parkinson’s disease and end-of-dose motor fluctuations whose symptoms cannot be stabilized on levodopa/dopa decarboxylase inhibitor combinations [5].

Associated Conditions
Pharmacodynamics

Opicapone (OPC) is a powerful, reversible, and strictly peripheral third-generation catechol-O-methyltransferase inhibitor (COMT) inhibitor, which improves levodopa (L-Dopa) availability. It serves as adjunct therapy for L-Dopa treated patients with Parkinson's disease and motor fluctuations [6].

Opicapone showed a significant (>90%) and long-lasting (>24 hours) COMT inhibition in healthy subjects after administration of a 50 mg dose [10].

In 14- to 15-week, double-blind, multinational trials and in 1-year, open-label studies, opicapone demonstrated to be an effective and generally well tolerated adjunct therapy to L-Dopa plus a dopa decarboxylase inhibitor and other Parkinson disease therapy. During the double-blind phase, adjunctive opicapone 50 mg once daily provided significantly greater improvements in motor fluctuations than placebo, with these improvements noninferior to those with entacapone. These beneficial improvements in motor fluctuations with opicapone were maintained in patients who continued adjunctive opicapone during the extension studies, with patients who switched from placebo or entacapone to opicapone experiencing significant improvements in motor fluctuations during this year [1].

Mechanism of action

Opicapone is a peripheral, selective and reversible catechol-O-methyltransferase (COMT) inhibitor endowed with a high binding affinity (sub-picomolar) that results in a slow complex dissociation rate constant and long-term action (>24 hours) in vivo [10].

In the presence of a DOPA decarboxylase inhibitor (DDCI), COMT acts as the primary metabolizing enzyme for levodopa, catalyzing the conversion to 3-O-methyldopa (3-OMD) in both the brain and periphery. In those taking levodopa and a peripheral DDCI, such as carbidopa or benserazide, opicapone augments levodopa plasma levels, thereby enhancing the efficacy of levodopa [10].

TargetActionsOrganism
ACatechol O-methyltransferase
antagonist
Human
Absorption

Oral opicapone demonstrates linear, dose-dependent absorption. However, following simultaneous ingestion of a high-fat, high-calorie meal, the maximal plasma concentration is decreased [6].

tmax of 1.0 h to 2.5 h after once-daily multiple-dose administration of up to 50 mg opicapone [10].

Volume of distribution

Approximately 30 L [L2431].

One study showed small systemic accumulation after multiple-dosing [2].

Protein binding

>99.7% [8]

Metabolism

Sulphation appears to be the main metabolic pathway for this drug [3]. Other metabolic pathways include reduction, methylation, and glucuronidation [8].

Opicapone undergoes N-oxide reduction to BIA 9-1079, an active metabolite, and this is the main metabolite in monkeys, and is less significant in rats and mice however. In humans, this metabolite is not detectable. However, human metabolism results in an an inactive metabolite BIA 9-1103, the result of 3-O-sulphation, and BIA 9-1104, the result of 4-O-methylation. BIA 9-1103 has been measured in mouse, rat and monkey samples, and BIA 9-1104 detected in negligible amounts in the mini-pig, rat and mouse samples, and therefore no unique human metabolites are present and all can be detected in at least one of the non-clinical species. Two have been examined with significance, BIA 9-1079 and BIA 9-1103 [8].

Route of elimination

Opicapone is predominantly eliminated as metabolites in feces [8].

Half life

1.58-4.50h [7]

Despite the short half-life, the observed half-life of opicapone-induced COMT inhibition in human red blood cells was 61.6 h (standard deviation [SD] = 37.6 h) [3].

Clearance

In a pharmacokinetic trial, fter oral administration, the total body clearance of opicapone at a dose of 50 mg was 22 L/h, with an inter-subject variability of 45% [10].

Toxicity

Dyskinesia was the most serious adverse event frequently associated with opicapone administration. The reported incidence was 24% in a placebo-controlled trial (vs 8% with placebo) and 16% in the comparative trial (versus 4% with placebo and 8% with entacapone). Some other adverse events include dizziness, dry mouth, as well as constipation [5].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Opicapone.
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Opicapone.
AzelastineThe metabolism of Azelastine can be decreased when combined with Opicapone.
BuprenorphineThe metabolism of Buprenorphine can be decreased when combined with Opicapone.
ChloroquineThe metabolism of Chloroquine can be decreased when combined with Opicapone.
ChlorpromazineThe therapeutic efficacy of Opicapone can be decreased when used in combination with Chlorpromazine.
CilostazolThe serum concentration of Cilostazol can be increased when it is combined with Opicapone.
ClozapineThe therapeutic efficacy of Opicapone can be decreased when used in combination with Clozapine.
Conjugated estrogensThe metabolism of Conjugated estrogens can be decreased when combined with Opicapone.
CyclophosphamideThe metabolism of Cyclophosphamide can be decreased when combined with Opicapone.
Food Interactions
Not Available

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. [PubMed:27498199]
  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. [PubMed:28322896]
  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. [PubMed:23248072]
  4. Neurocrine Biosciences Will File New Drug Application for Opicapone for Parkinson's Disease Based on Existing Pivotal Clinical Trial Data [Link]
  5. Opicapone:once-daily adjunctive therapy for Parkinson’s disease [Link]
  6. Pharmacokinetic drug evaluation of opicapone for the treatment of 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 information [Link]
  11. Pharmacological Profile of Opicapone, a Third Generation Nitrocatechol COMT Inhibitor, in the Rat [Link]
External Links
ChemSpider
24667564
BindingDB
50019329
ChEBI
134699
ChEMBL
CHEMBL1089318
Wikipedia
Opicapone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentParkinson's Disease (PD)2
1CompletedTreatmentEpilepsies1
1CompletedTreatmentParkinson2
1CompletedTreatmentParkinson's Disease (PD)23
2CompletedTreatmentParkinson's Disease (PD)2
3CompletedTreatmentParkinson's Disease (PD)2
3Unknown StatusTreatmentParkinson's Disease (PD)1
4RecruitingTreatmentParkinson's Disease With Wearing-off Motor Fluctuations1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral25 mg
CapsuleOral50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityminimalhttp://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002790/WC500209538.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.044 mg/mLALOGPS
logP3.28ALOGPS
logP3.05ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)5.97ChemAxon
pKa (Strongest Basic)-0.47ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area149.46 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity118.12 m3·mol-1ChemAxon
Polarizability37.42 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
show 12 more
Substituents
Phenyl-1,2,4-oxadiazole / Nitrophenol / Nitrobenzene / Catechol / Nitroaromatic compound / Polyhalopyridine / 1-hydroxy-4-unsubstituted benzenoid / 1-hydroxy-2-unsubstituted benzenoid / 2-halopyridine / Methylpyridine
show 24 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. [PubMed:27498199]
  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. [PubMed:16690967]
  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 information [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
Curator comments
Data supporting this enzyme induction is limited to in vitro studies.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. EMA assessment report [Link]
  2. Opicapone EMA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. EMA assessment report [Link]
  2. Opicapone EMA Label [File]

Drug created on October 17, 2016 15:26 / Updated on October 01, 2018 15:02