{{Short description|Chemical compound}} {{Use dmy dates|date=May 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Drugbox | image = Macitentan skeletal.svg | image_class = skin-invert-image | alt = | caption =

<!-- Clinical data --> | tradename = Opsumit | Drugs.com = {{drugs.com|monograph|macitentan}} | MedlinePlus = a615033 | DailyMedID = Macitentan | pregnancy_AU = X | pregnancy_category= | routes_of_administration = By mouth | ATC_prefix = C02 | ATC_suffix = KX04 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023}}</ref> | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM --> | legal_US = Rx-only | legal_US_comment = <ref name="Opsumit FDA label">{{cite web | title=Opsumit- macitentan tablet, film coated | website=DailyMed | date=22 September 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e484a50-55db-4b85-8c57-6cd1b0353abd | access-date=24 October 2020}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Opsumit EPAR">{{cite web | title=Opsumit EPAR | website=European Medicines Agency (EMA) | date=27 September 2011 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/opsumit | access-date=6 August 2024}}</ref>

<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = Hydrolysis, oxidation (CYP3A4) | elimination_half-life = | excretion = 2/3 urine, 1/3 faeces

<!-- Identifiers --> | CAS_number = 441798-33-0 | PubChem = 16004692 | DrugBank = DB08932 | ChemSpiderID = 13134960 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = Z9K9Y9WMVL | KEGG = D10135 | ChEBI = 76607 | ChEMBL = 2103873 | synonyms = ACT-064992

<!-- Chemical data --> | IUPAC_name = ''N''-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-''N'''-propylsulfamide | C=19 | H=20 | Br=2 | N=6 | O=4 | S=1 | smiles = Brc1ccc(cc1)c3c(ncnc3OCCOc2ncc(Br)cn2)NS(=O)(=O)NCCC | StdInChI = 1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27) | StdInChIKey = JGCMEBMXRHSZKX-UHFFFAOYSA-N }}

'''Macitentan''', sold under the brand name '''Opsumit''', is an endothelin receptor antagonist developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH).<ref name="Hong_2014">{{cite journal | vauthors = Hong IS, Coe HV, Catanzaro LM | title = Macitentan for the treatment of pulmonary arterial hypertension | journal = The Annals of Pharmacotherapy | volume = 48 | issue = 4 | pages = 538–47 | date = April 2014 | pmid = 24458948 | doi = 10.1177/1060028013518900 | s2cid = 24720486 }}</ref> Macitentan is a dual endothelin receptor antagonist, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ET<sub>A</sub> and ET<sub>B</sub>.<ref name="Hong_2014" /> However, macitentan has a 50-fold increased selectivity for the ET<sub>A</sub> subtype compared to the ET<sub>B</sub> subtype.<ref name="Iglarz_2008">{{cite journal | vauthors = Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, Weller T, Bolli MH, Boss C, Buchmann S, Capeleto B, Hess P, Qiu C, Clozel M | display-authors = 6 | title = Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 3 | pages = 736–45 | date = December 2008 | pmid = 18780830 | doi = 10.1124/jpet.108.142976 | s2cid = 6315900 }}</ref>

Macitentan was approved for medical use in the United States in October 2013.<ref name="Opsumit FDA label" /><ref>{{cite press release | url = http://www.actelion.com/en/our-company/news-and-events/index.page?newsId=1736781 | title = Actelion receives us fda approval of Opsumit (macitentan) for the treatment of pulmonary arterial hypertension | archive-url = https://web.archive.org/web/20131023060349/http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1736781 | archive-date=23 October 2013 | publisher = Actelion | access-date = 22 October 2013 }}</ref>

== Adverse effects == The FDA prescription label contains a boxed warning for embryo-fetal toxicity. It is only available to females in the US through a risk evaluation and mitigation strategy (REMS) program.<ref name="Opsumit FDA label" />

==Mechanism of action== {{Technical|section|date=March 2014}}

===Endothelin and endothelin receptors=== Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells.<ref name="Gatfield_2012">{{cite journal | vauthors = Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O | title = Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells | journal = PLOS ONE | volume = 7 | issue = 10 | article-number = e47662 | date = 2012 | pmid = 23077657 | pmc = 3471877 | doi = 10.1371/journal.pone.0047662 | bibcode = 2012PLoSO...747662G | doi-access = free }}</ref> In the lungs, the most common ET form released is ET-1.<ref name="Gatfield_2012" /> ET-1 release can occur through both constitutive and non-constitutive pathways.<ref name="Gatfield_2012" /> Upon release, ET-1 can bind to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs.<ref name="Gatfield_2012" /> ET receptors are G protein coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway.<ref name="Gatfield_2012" /> There are two receptor subtypes that endothelin will bind to: ETA and ETB. ETA is associated with cell growth and vasoconstriction while ETB is responsible for anti-proliferation of cells, vasodilation and ET-1 clearance. The rise in intracellular calcium leads to contraction of the arterial smooth muscle, as well as vascular remodelling due to cell proliferation.<ref name="Gatfield_2012" /> Prolonged constriction and fibrosis are factors in the pathogenesis of PAH.<ref name="Hong_2014" />

===Role of macitentan=== Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors. Blocking of the ETA receptor subtype seems to be of more importance in the treatment of PAH than blocking of ETB, likely because there are higher numbers of ETA receptors than ETB receptors in pulmonary arterial smooth muscle cells.<ref name="Gatfield_2012" /> The blocking of Endothelin 1 leads to vasodilation and decreases the proliferation of cells in the vessels of the arteries which contributes to the narrowing and leads to the pulmonary arterial hypertension.

==Pharmacokinetics== Macitentan is taken as a 10&nbsp;mg oral dose once a day.<ref name="Hong_2014" /> Its half-life in humans is about 16 hours and steady state is reached by the third day of administration.<ref name="Bruderer_2012">{{cite journal | vauthors = Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta PN, Treiber A, Dingemanse J | title = Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 42 | issue = 9 | pages = 901–10 | date = September 2012 | pmid = 22458347 | doi = 10.3109/00498254.2012.664665 | s2cid = 38365884 }}</ref> It is absorbed slowly into the plasma.<ref name="Sidharta_2011">{{cite journal | vauthors = Sidharta PN, van Giersbergen PL, Halabi A, Dingemanse J | title = Macitentan: entry-into-humans study with a new endothelin receptor antagonist | journal = European Journal of Clinical Pharmacology | volume = 67 | issue = 10 | pages = 977–84 | date = October 2011 | pmid = 21541781 | pmc = 3169777 | doi = 10.1007/s00228-011-1043-2 }}</ref> Macitentan dealkylates into the active metabolite aprocitentan (ACT-132577), which reaches its peak plasma concentration about 30 hours after the first dose is administered, and has a half-life of approximately 48 hours.<ref name="Sidharta_2011" /> Although aprocitentan has a lower affinity for the ET receptors than its parent compound,<ref name="Iglarz_2008" /> It maintains higher plasma concentrations than macitentan.<ref name="Sidharta_2011" /> Both compounds can be excreted from the body through the urine or feces.<ref name="Bruderer_2012" />

Co-administration of ciclosporin has only a slight effect on the concentrations of macitentan and its active metabolite, while rifampicin decreases the area under the curve (AUC) of the drug's blood plasma concentration by 79%, and ketoconazole approximately doubles it. This corresponds to the finding that macitentan is mainly metabolised via the liver enzyme CYP3A4.<ref>{{cite journal | vauthors = Bruderer S, Aänismaa P, Homery MC, Häusler S, Landskroner K, Sidharta PN, Treiber A, Dingemanse J | display-authors = 6 | title = Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist | journal = The AAPS Journal | volume = 14 | issue = 1 | pages = 68–78 | date = March 2012 | pmid = 22189899 | pmc = 3282010 | doi = 10.1208/s12248-011-9316-3 }}</ref>

thumb|left|Aprocitentan, the active metabolite of macitentan {{clear-left}}

===Experimental pharmacokinetics=== Macitentan has slow association kinetics.<ref name="Gatfield_2012" /> Its potency increases 6.3-fold when it is pre-incubated with pulmonary arterial smooth muscle cells for 120 minutes compared to 10 minutes with pulmonary arterial smooth muscle cells.<ref name="Gatfield_2012" /> Macitentan also has a high receptor occupancy half-life (approximately 17 minutes) compared to bosentan (approximately 70 seconds) and ambrisentan (approximately 40 seconds).<ref name="Gatfield_2012" /> This increased receptor occupancy half-life allows macitentan to act as a non-competitive antagonist of ET receptors.<ref name="Gatfield_2012" /> Bosentan and ambrisentan are both competitive antagonists.<ref name="Gatfield_2012" />

== References == {{reflist}}

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Category:Endothelin receptor antagonists Category:Pyrimidines Category:Sulfamides Category:Drugs developed by Johnson & Johnson Category:4-Bromophenyl compounds Category:Orphan drugs Category:Bromoarenes