A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension

Abstract

The approval of macitentan has increased the number of pharmacological treatments of pulmonary arterial hypertension (PAH). Here, we review the effect on PAH of macitentan compared to other endothelin receptor antagonists. Drugs targeting the endothelin (ET) pathway include the selective ET receptor antagonist ambrisentan, the ET /ET receptor antagonists, bosentan and macitentan, which were recently approved for PAH treatment. Macitentan exhibits higher antagonistic potency than bosentan and ambrisentan in pulmonary smooth muscle cells. Compared to ambrisentan and bosentan, macitentan has a longer duration of action, reflected by the longer half-life, as well as pharmacodynamics attributed to its active metabolite, ACT-132577. The efficacy of macitentan on PAH was investigated in the phase III SERAPHIN trial (NCT00660179). Macitentan significantly reduced morbidity and mortality. It improved the 6-min. walk distance (6MWD) among PAH patients. In the AMB-320/321-E (NCT00578786) study, ambrisentan improved exercise capacity. In the EARLY study (NCT00091715), bosentan showed improvements in 6MWD which were not statistically significant. Bosentan had an effect on PAH in patients with Eisenmenger syndrome (ES) in the BREATHE-5 study (NCT00367770), while macitentan did not improve 6MWD in these patients, but there are differences regarding study size and functional class, and that 30% of the patients treated with macitentan were already in treatment with a phosphodiesterase type 5 inhibitor. Macitentan revealed a lower risk of developing peripheral oedema and hepatotoxicity in the SERAPHIN study. In summary, macitentan has an efficiency comparable to bosentan and ambrisentan in the treatment of PAH. Patients treated with macitentan exhibited less adverse effects compared to bosentan and ambrisentan. In patients with PAH associated with ES, the trials with bosentan and macitentan do not seem comparable, and it needs to be clarified whether these drugs are effective when administered as part of a combination treatment in this condition.

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

“…At the cellular level, the drug differs from bosentan and ambrisentan through its binding profile, namely its slow receptor dissociation characteristics [36]. Due to this quality, macitentan theoretically has the potential to block ET-1-induced signaling more effectively than other ERAs [37].…”

“…Macitentan is administrated orally once daily, with a usual dosage of 10 mg [41]. The drug is slowly absorbed, reaching C max approximately 8 h post-dose, and more than 99% is bound to plasma proteins [37]. Although the bioavailability is unknown, data from physiologically based pharmacokinetic modelling indicates high oral bioavailability.…”

“…Macitentan has one active metabolite, ACT-132577 (also referred as aprocitentan), which is also an ET A /ET B receptor antagonist [36]. Macitentan has a terminal half-life of 16 h [37], before the drug and its metabolites are excreted in the feces (24%) and urine (50%) [28,37].…”

Functional characterization of 27 CYP3A4 variants on macitentan metabolism in vitro

“…The metabolite of macitentan was analysed by ultra performance liquid chromatography-tandem mass spectrometry. Key finding Most CYP3A4 protein variants () exhibited a sharp decrease, meanwhile nearly one in five variants (CYP3A4.3,.4,.5,.10,.15,.16) showed a significant rise in intrinsic clearance. The relative clearance of CYP3A4 protein variants was ranged from 5.53 to 501.00%.…”

“…Compared to the selective ETA receptor antagonist ambrisentan, the ETA/ETB receptor antagonists bosentan, macitentan exhibits higher antagonistic potency, has a longer duration of action, reflected by the longer half-life, as well as pharmacodynamics attributed to its active metabolite, and exhibits less adverse effects. [5] Except treating PAH, Tullos et al also found macitentan had an ability to decrease renal injury by protecting renal microenvironment. [6] Cytochrome P450 (CYP450) is considered to be one of approaches to metabolite a large quantity of drugs.…”