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).[4] Macitentan is a dual endothelin receptor antagonist, 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]
Macitentan was approved for medical use in the United States in October 2013.[2][6]
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.[2]
Mechanism of action
Endothelin and endothelin receptors
Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells.[7] In the lungs, the most common ET form released is ET-1.[7] ET-1 release can occur through both constitutive and non-constitutive pathways.[7] Upon release, ET-1 can bind to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs.[7] ET receptors are G protein coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway.[7] 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.
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.[8] It is absorbed slowly into the plasma.[9] 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.[9] Although aprocitentan has a lower affinity for the ET receptors than its parent compound,[5] It maintains higher plasma concentrations than macitentan.[9] Both compounds can be excreted from the body through the urine or feces.[8]
References
- Prescription medicines: registration of new chemical entities in Australia, 2014 Therapeutic Goods Administration (TGA), 21 June 2022, retrieved 10 April 2023^
- Opsumit- macitentan tablet, film coated DailyMed, 22 September 2020, retrieved 24 October 2020^
- Opsumit EPAR