Macitentan, sold under the brand name Opsumit, is an

endothelin receptor antagonist An endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors. Three main kinds of ERAs exist: * selective ETA receptor antagonists ( sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan, edonentan), which affect e ...

(ERA) developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH). The other two ERAs marketed as of 2014 are

bosentan Bosentan, sold under the brand name Tracleer and Safebo among others, is a dual endothelin receptor antagonist medication used in the treatment of pulmonary artery hypertension (PAH). Bosentan is available as film-coated tablets (62.5 mg o ...

and ambrisentan. Macitentan is a dual ERA, meaning that it acts as an antagonist of two

endothelin 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 ...

(ET) receptor subtypes, ET_A and ET_B. However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype. The drug received approval from the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) on October 13, 2013. Macitentan is available as a generic medication in the United States as of April 2021.

Adverse effects

The FDA has issued a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

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.

Mechanism of action

Endothelin and endothelin receptors

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

Gαq Gq protein alpha subunit is a family of heterotrimeric G protein G alpha subunit, alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits ...

signaling pathway. 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. Prolonged constriction and fibrosis are factors in the pathogenesis of PAH.

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. The blocking of Endothelin 1 leads to vasodilation and decreases the proliferation of cells in the vessels of the artries 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. Its half-life in humans is about 16 hours and steady state is reached by the third day of administration. It is absorbed slowly into the plasma. Macitentan dealkylates into the active metabolite 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. Although ACT-132577 has a lower affinity for the ET receptors than its parent compound, It maintains higher plasma concentrations than macitentan. Both compounds can be excreted from the body through the urine or feces. Co-administration of

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...

has only a slight effect on the concentrations of macitentan and its active metabolite, while rifampicin decreases the

area under the curve In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...

(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. ACT-132577 skeletal

Experimental pharmacokinetics

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

References

External links

* {{Portal bar , Medicine Endothelin receptor antagonists Pyrimidines Sulfamides Johnson & Johnson brands Bromoarenes