Macitentan

Last updated
Macitentan
Macitentan skeletal.svg
Clinical data
Trade names Opsumit
Other namesACT-064992
AHFS/Drugs.com Monograph
MedlinePlus a615033
License data
Pregnancy
category
  • AU:X (High risk)
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Hydrolysis, oxidation (CYP3A4)
Excretion 2/3 urine, 1/3 faeces
Identifiers
  • N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H20Br2N6O4S
Molar mass 588.28 g·mol−1
3D model (JSmol)
  • Brc1ccc(cc1)c3c(ncnc3OCCOc2ncc(Br)cn2)NS(=O)(=O)NCCC
  • InChI=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)
  • Key:JGCMEBMXRHSZKX-UHFFFAOYSA-N

Macitentan, sold under the brand name Opsumit, is an endothelin receptor antagonist (ERA) developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH). [4] The other two ERAs marketed as of 2014 are bosentan and ambrisentan. [4] Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB. [4] However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype. [5] The drug received approval from the U.S. Food and Drug Administration (FDA) on October 13, 2013. [6]

Contents

Macitentan is available as a generic medication in the United States as of April 2021. [7]

Adverse effects

The FDA has issued a black box warning for macitentan for embryo-fetal toxicity. It is only available to females in the U.S through a risk evaluation and mitigation strategy (REMS) program. [8]

Mechanism of action

Endothelin and endothelin receptors

Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells. [9] In the lungs, the most common ET form released is ET-1. [9] ET-1 release can occur through both constitutive and non-constitutive pathways. [9] Upon release, ET-1 can bind to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs. [9] ET receptors are G protein coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway. [9] 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. [9] Prolonged constriction and fibrosis are factors in the pathogenesis of PAH. [4]

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. [9] 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 mg oral dose once a day. [4] Its half-life in humans is about 16 hours and steady state is reached by the third day of administration. [10] It is absorbed slowly into the plasma. [11] 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. [11] Although aprocitentan has a lower affinity for the ET receptors than its parent compound, [5] It maintains higher plasma concentrations than macitentan. [11] Both compounds can be excreted from the body through the urine or feces. [10]

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. [12]

Aprocitentan, the active metabolite of macitentan Aprocitentan.svg
Aprocitentan, the active metabolite of macitentan

Experimental pharmacokinetics

Macitentan has slow association kinetics. [9] 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. [9] Macitentan also has a high receptor occupancy half-life (approximately 17 minutes) compared to bosentan (approximately 70 seconds) and ambrisentan (approximately 40 seconds). [9] This increased receptor occupancy half-life allows macitentan to act as a non-competitive antagonist of ET receptors. [9] Bosentan and ambrisentan are both competitive antagonists. [9]

Related Research Articles

<span class="mw-page-title-main">Pulmonary hypertension</span> Increased blood pressure in lung arteries

Pulmonary hypertension is a condition of increased blood pressure in the arteries of the lungs. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual. According to the definition at the 6th World Symposium of Pulmonary Hypertension in 2018, a patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 20mmHg at rest, revised down from a purely arbitrary 25mmHg, and pulmonary vascular resistance (PVR) greater than 3 Wood units.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

<span class="mw-page-title-main">Sitaxentan</span> Chemical compound

Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH). It was marketed as Thelin by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity.

An endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors.

<span class="mw-page-title-main">Endothelin</span>

Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.

<span class="mw-page-title-main">Bosentan</span> Medication

Bosentan, sold under the brand name Tracleer among others, is a dual endothelin receptor antagonist medication used in the treatment of pulmonary artery hypertension (PAH).

<span class="mw-page-title-main">Iloprost</span> Pharmaceutical drug

Iloprost, sold under the brand name Ventavis among others, is a medication used to treat pulmonary arterial hypertension (PAH), scleroderma, Raynaud's phenomenon, frostbite, and other conditions in which the blood vessels are constricted and blood cannot flow to the tissues. Iloprost is a prostacyclin mimetic.

Portopulmonary hypertension (PPH) is defined by the coexistence of portal and pulmonary hypertension. PPH is a serious complication of liver disease, present in 0.25 to 4% of all patients with cirrhosis. Once an absolute contraindication to liver transplantation, it is no longer, thanks to rapid advances in the treatment of this condition. Today, PPH is comorbid in 4-6% of those referred for a liver transplant.

There are at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC, all of which are G protein-coupled receptors whose activation result in elevation of intracellular-free calcium, which constricts the smooth muscles of the blood vessels, raising blood pressure, or relaxes the smooth muscles of the blood vessels, lowering blood pressure, among other functions.

<span class="mw-page-title-main">Ambrisentan</span> Chemical compound

Ambrisentan, sold under the brand name Letairis among others, is a drug used for the treatment of pulmonary hypertension. It is an endothelin receptor antagonist.

<span class="mw-page-title-main">Endothelin 1</span>

Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells. The protein encoded by this gene – EDN1 – is proteolytically processed to release endothelin 1. Endothelin 1 is one of three isoforms of human endothelin.

<span class="mw-page-title-main">Atrasentan</span> Chemical compound

Atrasentan is an experimental drug that is being studied for the treatment of various types of cancer, including non-small cell lung cancer. It is also being investigated as a therapy for diabetic kidney disease.

<span class="mw-page-title-main">Endothelin receptor type B</span> Protein-coding gene in the species Homo sapiens

Endothelin receptor type B, (ET-B) is a protein that in humans is encoded by the EDNRB gene.

<span class="mw-page-title-main">Terguride</span> Chemical compound

Terguride, sold under the brand name Teluron, is a serotonin receptor antagonist and dopamine receptor agonist of the ergoline family. It is approved for and used as a prolactin inhibitor in the treatment of hyperprolactinemia in Japan. Terguride is taken by mouth.

<span class="mw-page-title-main">Riociguat</span> Chemical compound

Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylate cyclase (sGC). It is used to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of the class of sGC stimulators. The drug has a half-life of 12 hours and will decrease dyspnea associated with pulmonary arterial hypertension.

<span class="mw-page-title-main">PRX-08066</span> Chemical compound

PRX-08066 is a drug discovered and developed by Predix Pharmaceuticals [Dale S. Dhanoa et al. Patent US 7,030,240 B2], which acts as a potent and selective antagonist at the serotonin 5-HT2B receptor, with a 5-HT2Bbinding affinity (Ki) of 3.4nM, and high selectivity over the closely related 5-HT2A and 5-HT2C receptors and other receptor targets. PRX-08066 and other selective 5-HT2B antagonists are being researched for the treatment of pulmonary arterial hypertension, following the discovery that the potent 5-HT2B agonist norfenfluramine produces pulmonary arterial hypertension and subsequent heart valve damage. In animal studies, PRX-08066 has been found to reduce several key indicators of pulmonary arterial hypertension and improved cardiac output, with similar efficacy to established drugs for this condition such as bosentan, sildenafil, beraprost and iloprost. It is also being researched for potential anti-cancer applications, due to its ability to inhibit fibroblast activation.

<span class="mw-page-title-main">Actelion</span> Swiss biopharmaceutical company

Actelion is a pharmaceuticals and biotechnology company established in December 1997, headquartered in Allschwil near Basel, Switzerland.

<span class="mw-page-title-main">Selexipag</span> Chemical compound

Selexipag, sold under the brand name Uptravi, is a medication developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679, are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation. It is taken by mouth or administered intravenously.

<span class="mw-page-title-main">Sarafotoxin</span> Protein toxin family

Sarafotoxins (SRTXs) are a group of toxins present in the venom of Atractaspis engaddensis, and in clinical trials cause similar symptoms to patients diagnosed with acute giardiasis. Their etymology is from the name of the snake "שרף עין גדי" in Hebrew, pronounced "Saraf Ein Gedi". Together with endothelins (ETs), they form a homogenous family of strong vasoconstrictor isopeptides. Among them, a few slightly different substances can be named as SRTX-a, SRTX-b, SRTX-c, which were initially derived from A. engaddensis. Each one contains twenty-one amino acid residues that spontaneously fold into a defined tertiary structure, with two interchain-cysteine linkages and a long hydrophobic tail. There are also other compounds, however, they are mostly derivations of previously mentioned ones. The main differences in the family of endothelin and sarafotoxins appear at N-terminal of peptides, as C-terminal in all of them is almost the same.

<span class="mw-page-title-main">Aprocitentan</span> Chemical compound

Aprocitentan, sold under the brand name Tryvio, is a medication used for the treatment of hypertension. It is an endothelin receptor antagonist active at both endothelin A and endothelin B receptors. It is developed for resistant hypertension by Idorsia, which sold it to Janssen but purchased the rights back in 2023 for $343 million.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. ↑ "Opsumit- macitentan tablet, film coated". DailyMed. 22 September 2020. Retrieved 24 October 2020.
  4. 1 2 3 4 5 Hong IS, Coe HV, Catanzaro LM (April 2014). "Macitentan for the treatment of pulmonary arterial hypertension". The Annals of Pharmacotherapy. 48 (4): 538–47. doi:10.1177/1060028013518900. PMID   24458948. S2CID   24720486.
  5. 1 2 Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, et al. (December 2008). "Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 736–45. doi:10.1124/jpet.108.142976. PMID   18780830. S2CID   6315900.
  6. ↑ "Actelion receives us fda approval of Opsumit (macitentan) for the treatment of pulmonary arterial hypertension". Actelion. Archived from the original on 2013-10-23. Retrieved 22 October 2013.
  7. ↑ "Macitentan: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 19 June 2021.
  8. ↑ Opsumit [package insert] Whippany, NJ: Bayer HealthCare Pharmaceuticals 2017
  9. 1 2 3 4 5 6 7 8 9 10 11 12 Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O (2012). "Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells". PLOS ONE. 7 (10): e47662. Bibcode:2012PLoSO...747662G. doi: 10.1371/journal.pone.0047662 . PMC   3471877 . PMID   23077657.
  10. 1 2 Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta PN, Treiber A, Dingemanse J (September 2012). "Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 42 (9): 901–10. doi:10.3109/00498254.2012.664665. PMID   22458347. S2CID   38365884.
  11. 1 2 3 Sidharta PN, van Giersbergen PL, Halabi A, Dingemanse J (October 2011). "Macitentan: entry-into-humans study with a new endothelin receptor antagonist". European Journal of Clinical Pharmacology. 67 (10): 977–84. doi:10.1007/s00228-011-1043-2. PMC   3169777 . PMID   21541781.
  12. ↑ Bruderer S, Aänismaa P, Homery MC, Häusler S, Landskroner K, Sidharta PN, et al. (March 2012). "Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist". The AAPS Journal. 14 (1): 68–78. doi:10.1208/s12248-011-9316-3. PMC   3282010 . PMID   22189899.
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