SUMMARY

• OPSUMIT is a dual endothelin (ET)_A/ET_B receptor antagonist.¹
• There are currently no large clinical studies comparing the safety and efficacy of selective vs nonselective endothelin receptor antagonists (ERAs).

AVAILABLE DATA

Background

OPSUMIT is a dual ET_A/ET_B receptor antagonist designed to optimize safety and efficacy.¹ Studies have shown that macitentan exhibits sustained binding to ET receptors in human pulmonary arterial smooth muscle cells.^2,3 Additionally, testing of macitentan in animal models of pulmonary hypertension showed amelioration of disease.^3-5

Macitentan 10 mg Binding Kinetics vs Other Marketed ERAs

Iglarz et al (2008)³ investigated the relative tissue targeting potential of macitentan, ambrisentan, and bosentan by measuring and comparing log D and pK_a, which are used as markers for tissue penetration. Macitentan exhibited higher pK_a and log D and had a higher nonionized fraction than either bosentan or ambrisentan at pH 7.4. Please refer to Table: Physicochemical Parameters of Macitentan, Bosentan, and Ambrisentan below for these results.

Pharmacokinetics

Gatfield et al (2012)² investigated the dissociation kinetics of macitentan, bosentan, and ambrisentan in pulmonary arterial smooth muscle cells (PASMC) calcium release assays and found that macitentan displayed significantly slower receptor dissociation kinetics, as demonstrated by a 15-fold higher receptor occupancy half-life (ROt_½) vs ambrisentan or bosentan. Calculated receptor occupancy half-lives were 70 seconds for bosentan, 40 seconds for ambrisentan, and 17 minutes for macitentan. Macitentan lost potency slowly over time and was still highly potent 60 minutes after washout.

Due to its slower dissociation rate, macitentan, unlike bosentan or ambrisentan, remains effective at blocking ET receptors, even when ET-1 concentrations are high, which is characteristic of pulmonary arterial hypertension disease conditions.² Concentration-response curves generated from in vitro inositol-1-phosphate (IP1) accumulation assays show that bosentan, ambrisentan, and macitentan blocked IP1 accumulation induced by 20 minutes of ET-1 stimulation. Under these experimental conditions, bosentan and ambrisentan displayed surmountable antagonism, as evidenced by a rightward shift of ET-1 concentration-response curves, while macitentan displayed insurmountable antagonism. See the figure, Effect on ET-1 Induced IP₁ Accumulation After 20 Minutes of Stimulation, in the publication for more information.² When ET-1 stimulation time was increased to 90 minutes, macitentan behaved as a surmountable antagonist. Further research by Gatfield et al (2012) on the structure-activity relationship of macitentan and the ET_A receptor revealed unique receptor engagement, distinct from other ERAs. Macitentan’s binding is characterized by dominating hydrophobic interactions and fewer electrostatic forces, resulting in its increased occupancy in insurmountable antagonism.⁶

Information From a Literature Search

Gatfield et al (2012, 2014)^2,6 looked at the distinct ET_A receptor binding mode of macitentan as determined by site directed mutagenesis. Gatfield et al (2012) also looked at how the slow receptor dissociation kinetics differentiate macitentan from other ERAs in PASMC. Bruderer et al (2012)⁷explored the absorption, distribution, metabolism, and excretion of macitentan in humans. Sidharta et al (2011)⁸ conducted a double-blind, placebocontrolled study to analyze the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan in healthy male patients. Raja et al (2008) and Iglarz et al (2010)^3,9discussed the pharmacology of macitentan. Kummer et al (2009)¹⁰ compared the dissolution and pharmacokinetic profiles of two galenical formulations of macitentan.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 24 January 2025.