Opicapone

Opicapone is a drug which is a catechol-O-methyltransferase (COMT) inhibitor.

Opicapone
It is administered together with levodopa in patients with Parkinson's disease. In
June 2016 it was authorised for sale – under the trade name Ongentys – in the
European Union.[1] In February 2017, its developer Bial sold exclusive
marketing rights for the United States and Canada to Neurocrine Biosciences for
an initial payment of $30 million.[2]

Clinical data
Contents Trade names Ongentys
Medical uses Synonyms BIA 9-1067
Contraindications AHFS/Drugs.com UK Drug
Side effects Information (http
Overdose s://www.drugs.co
Interactions m/uk/ongentys.ht
Pharmacology ml)
Mechanism of action
License data EU EMA: by INN
Pharmacokinetics
(http://www.ema.
References
europa.eu/ema/in
dex.jsp?curl=%2F
pages%2Fmedici
Medical uses nes%2Flanding%
The COMT inhibitor opicapone is used as an additive to a combination of 2Fepar_search.js
levodopa and a DOPA decarboxylase inhibitor to treat patients with Parkinson's p&mid=&searchT
disease experiencing end-of-dose motor fluctuations, if they cannot be stabilised ab=searchByKey
with this drug combination.[3] &alreadyLoaded=
true&isNewQuery
Contraindications =true&status=Aut
horised&status=
This drug is contraindicated in people with cancers that secrete catecholamines Withdrawn&statu
(for example epinephrine), such as phaeochromocytoma or paraganglioma, s=Suspended&st
because as a COMT inhibitor it blocks catecholamine degradation. Other atus=Refused&ke
contraindications are a history of neuroleptic malignant syndrome (NMS) or ywordSearch=Su
non-traumatic rhabdomyolysis, and combination with monoamine oxidase bmit&searchType
inhibitors that are not used as antiparkinsonians, because of possible drug =inn&taxonomyP
interactions.[3] ath=&treeNumber
=&searchGeneric
NMS and associated rhabdomyolysis have been rarely observed under the older
Type=generics&k
COMT inhibitors tolcapone and entacapone. This typically occurs shortly after
eyword=Opicapo
the beginning of a COMT inhibitor add-on therapy when the levodopa dose has
ne)
been reduced, or after discontinuation of a COMT inhibitor.[4]
Routes of By mouth
 administration (capsules)
Side effects
ATC code N04BX04 (WHO
People taking opicapone very commonly (18%) experience dyskinesia. Other
(https://www.who
common side effects (in 1 to 10% of patients) include dizziness, strange dreams,
cc.no/atc_ddd_in
hallucinations, constipation, dry mouth, orthostatic hypotension (low blood
dex/?code=N04B
pressure), and muscle spasms.[3] Apart from spasms, these side effects are also
X04))
known from tolcapone and entacapone.[4]
Legal status
As with entacapone, no relevant liver toxicity has been found in studies. This is Legal status UK: POM
in contrast to the first COMT inhibitor tolcapone, which could cause – in some
(Prescription
cases lethal – liver insufficiency.[4][5]
only)
Pharmacokinetic data
Overdose
Bioavailability ~20%
No specific antidote is known.[3]
Protein binding 99.9%
Metabolism Mainly sulfation,
Interactions also reduction,
Monoamine oxidase inhibitors (MAO inhibitors) are another class of drugs glucuronidation,
blocking catecholamine degradation. Therefore, their combination with methylation
opicapone can result in increased catecholamine concentrations in the body and Elimination 0.7 to 3.2 hours
corresponding adverse effects. Combining the antiparkinson MAO inhibitors half-life
selegiline or rasagiline with opicapone is considered safe. Potentially, there are Duration of >24 hours
action
also interactions with drugs being metabolised by COMT (for example
Excretion Faeces (67%),
isoprenaline, epinephrine, dopamine, or dobutamine), tricyclic antidepressants
urine (13%)
and antidepressants of the norepinephrine reuptake inhibitor type. Possible
pharmacokinetic interactions are with substrates of the liver enzyme CYP2C8, Identifiers
such as repaglinide, and the transporter protein SLCO1B1, such as IUPAC name
simvastatin.[3] 5-[3-(2,5-Dichloro-4,6-dimethyl-1-oxido-3-pyrid
inyl)-1,2,4-oxadiazol-5-yl]-3-nitro-1,2-benz

Pharmacology enediol

CAS Number 923287-50-7 (htt

p://www.common
Mechanism of action
chemistry.org/Ch
Opicapone blocks the enzyme catechol-O-methyltransferase (COMT) effectively
emicalDetail.asp
(>90% at therapeutic doses), selectively and reversibly, and only outside the
x?ref=923287-50-
central nervous system. It dissociates slowly from COMT, resulting in a duration
7)
of action longer than 24 hours despite its short blood plasma half-life.[3][5] As
PubChem CID 15602694 (http
COMT and DOPA decarboxylase are the main enzymes for degrading levodopa,
blocking the two effectively increases its concentrations in the bloodstream. s://pubchem.ncbi.
More levodopa reaches the brain, where it is activated to dopamine.[6] nlm.nih.gov/comp
ound/15602694)
DrugBank DB11632 (https://
Pharmacokinetics
www.drugbank.c
The substance is quickly absorbed from the gut, but only to about 20% of the a/drugs/DB1163
applied dose. Highest blood plasma concentrations are reached after 1 to 2.5 2)
hours. When in the bloodstream, it is almost completely (99.9%) bound to
ChemSpider 24667564 (http://
plasma proteins, but apparently to different binding sites than warfarin, digoxin
and other drugs with high plasma protein affinity. It is mainly metabolised to the www.chemspider.
sulfate, which accounts for 67% of the circulating drug after a single dose, and a com/Chemical-Str
methylated derivative, which accounts for 21%. Minor metabolites are a reduced ucture.24667564.
derivative (<10%) and a glucuronide. All of these metabolites are inactive except html)
the reduced derivative. Opicapone is eliminated with a terminal half-life of 0.7 to UNII Y5929UIJ5N (http
3.2 hours. It is mainly excreted via the faeces (67%), and in form of the
s://fdasis.nlm.nih.
glucuronide also via the kidney (13%). The sulfate has a much longer half-life of
gov/srs/srsdirect.j
94 to 122 hours.[3][5][7]
sp?regno=Y5929
Opicapone sulfate is transported by SLCO1B1; the possibility that it blocks this UIJ5N)
transporter has not been excluded. Opicapone itself and the sulfate are also KEGG D10825 (http://w
transported by a number of other proteins, but given the low concentrations of ww.kegg.jp/entry/
the free substances in the blood plasma, this is very unlikely to give rise to drug D10825)
interactions. Opicapone is a weak inhibitor of the liver enzymes CYP1A2,
ChEBI CHEBI:134699 (h
CYP2B6, CYP2C8, and CYP2C9. The only CYP interaction found in studies
that is somewhat likely to be relevant is that with repaglinide, which is
ttps://www.ebi.ac.
metabolised by CYP2C8. The metabolism of warfarin, a CYP2C9 substrate, is
uk/chebi/searchI
not measurably affected.[3]
d.do?chebiId=CH
EBI:134699)
ChEMBL
References ChEMBL1089318
(https://www.ebi.a
1. Neurocrine Nabs BIAL's PD Therapy Opicapone for North America c.uk/chembldb/in
(http://www.genengnews.com/gen-news-highlights/neurocrine-nabs- dex.php/compoun
bials-pd-therapy-opicapone-for-north-america/81253859). Genetic
d/inspect/ChEMB
Engineering & Biotechnology News. Accessed April 2017.
L1089318)
2. [s.n.] (9 February 2017). Brief: Neurocrine and Bial reports exclusive
North American licensing agreement for opicapone (https://www.reut Chemical and physical data
ers.com/article/idUSFWN1FU12N). Reuters. Accessed April 2017. Formula C15H10Cl2N4O6
3. "Ongentys: EPAR – Product Information" (http://www.ema.europa.eu/
Molar mass 413.17
docs/en_GB/document_library/EPAR_-_Product_Information/human/
002790/WC500209536.pdf) (PDF). European Medicines Agency. 2 g/mol g·mol−1
February 2017. 3D model Interactive image
4. Haberfeld, H, ed. (2017). Austria-Codex (in German). Vienna: (JSmol)
(https://chemapp
Österreichischer Apothekerverlag. Comtan, Tasmar.
s.stolaf.edu/jmol/j
5. Annus, Á; Vécsei, L (2017). "Spotlight on opicapone as an adjunct to mol.php?model=
levodopa in Parkinson's disease: design, development and potential
CC1%3D%5BN%
place in therapy" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC523
4693). Drug Des Devel Ther. 11: 143–151. 2B%5D%28%5B
doi:10.2147/DDDT.S104227 (https://doi.org/10.2147%2FDDDT.S104 O-%5D%29C%2
227). PMC 5234693 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC 8Cl%29%3DC%2
5234693). PMID 28123288 (https://www.ncbi.nlm.nih.gov/pubmed/28 8C2%3DNOC%2
123288). 8C3%3DCC%2
6. Mutschler, Ernst; Schäfer-Korting, Monika (2001). 8%5BN%2B%5
Arzneimittelwirkungen (in German) (8 ed.). Stuttgart:
D%28%5BO-%5
Wissenschaftliche Verlagsgesellschaft. p. 315. ISBN 3-8047-1763-2.
D%29%3DO%2
7. Rocha, JF (2013). "Opicapone: a short lived and very long acting
9%3DC%28O%2
novel catechol-O-methyltransferase inhibitor following multiple dose
administration in healthy subjects" (https://www.ncbi.nlm.nih.gov/pm 9C%28O%29%3
c/articles/PMC3853535). Br J Clin Pharmacol. 76 (5): 763–775. DC3%29%3DN
doi:10.1111/bcp.12081 (https://doi.org/10.1111%2Fbcp.12081).
PMC 3853535 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC38535
 35). PMID 23336248 (https://www.ncbi.nlm.nih.gov/pubmed/2333624 2%29C%28C%2
8). 9%3DC1Cl)

SMILES
CC1=[N+]([O-])C(Cl)=C(C2=NOC(C3=CC([N+]
([O-])=O)=C(O)C(O)=C3)=N2)C(C)=C1Cl

InChI
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/h3-4,22-23
H,1-2H3

Opicapone and some of its metabolites: the main inactive metabolite

opicapone sulfate (BIA 9-1103), the active reduced derivative (BIA 9-1079),
and the inactive glucuronide (BIA 9-1106).[7]

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