Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?

Figures & data

Table 1 Pharmacodynamic or pharmacokinetic differences among endothelin (ET)-receptor antagonists

Parameters	Ambrisentan (Volibris)	Bosentan (Tracleer)	Macitentan (Opsumit)
Molecular weight	378.4 g/mol	551.6 g/mol	588.27 g/mol
Acid-dissociation constant (pKa)^Citation1	3.5	5.1	6.2
Acid or basic^Citation1	Acid	Moderately acid	Moderately neutral
Distribution coefficient (logD)^Citation1	−0.4	1.3	2.9
Receptor antagonism^Citation2	Selective for ETA receptor	Unselective for ETA and ETB receptors	Unselective for ETA and ETB receptors
Receptor selectivity (ETA:ETB)^Citation2	100:1	20:1	50:1
Type of antagonism^Citation1	Competitive antagonist	Competitive antagonist	Uncompetitive antagonist
Receptor occupancy (t½), minutes^Citation1	~1	~1	~17
Receptor association/dissociation^Citation1	Fast	Fast	Slow
Inhibition (IC50), nM^Citation1	2.8	12	1.2
Prodrug	–	–	–
Metabolism^Citation4^–^Citation6	CYP3A4, CYP3A5, CYP2C19^Citation4	CYP2C9, CYP3A4^Citation5	CYP3A4, CYP2C8, CYP2C9, CYP2C19^Citation6
Active metabolite^Citation2,Citation3	–	Ro48-5033 (hydroxybosentan)	ACT-132577^Citation2
Administration^Citation4^–^Citation6	Oral^Citation4	Oral^Citation5	Oral^Citation6
Onset of action (Cmax), hours ^Citation4^–^Citation6	1.5^Citation4	3–5^Citation5	8^Citation6
Bioavailability^Citation4^–^Citation6	–	50%^Citation5	–
Protein binding^Citation2	98.8% (binds primarily to albumin and to a lesser extent to α1-acid glycoprotein)^Citation4	>98% (binds to albumin) ^Citation5	>99% (binds primarily to albumin and to a lesser extent to α1-acid glycoprotein)^Citation6
Elimination^Citation4^–^Citation6	~80% of administered dose recovered in bile after 22% renal elimination^Citation4	~90% of administered dose recovered in bile after 3% renal elimination^Citation5	~50% of administered dose recovered in bile and urine ^Citation6

Table 2 Disadvantages and advantages of endothelin (ET)-receptor antagonists

Parameters	Ambrisentan (Volibris)	Bosentan (Tracleer)	Macitentan (Opsumit)
Oral administration	Once daily	Twice daily	Once daily
Need for monitoring of transaminases	++−	+++	−++
Need for hemoglobin monitoring	+++	+++	+++
Selectivity ratio for ETA (ETA: ETB)	200:1	20:1	50:1
Antagonist for ETA and ETB	− − −	+++	+++
Prevalent type of elimination	Biliary system	Biliary system	Kidneys
Peripheral edema	+++−	++−	+− − −
Drug interactions	+− − −	+++−	++− −
Contraindications	Child–Pugh C, pregnancy, breastfeeding, idiopathic pulmonary fibrosis	Child–Pugh B–C, pregnancy, concomitant cyclosporine A	Child–Pugh C, pregnancy, breastfeeding
Results confirmed by trials with composite primary end point (morbidity and mortality)	+++	− − −	+++

Table 3 Ongoing studies using macitentan

Studies	Participants
TOMORROW, NCT 02932410	Pulmonary arterial hypertension in pediatric population
PORTICO, NCT 02382016	Portopulmonary hypertension
OPUS,^Citation56	Registry
SYMPHONY, NCT 01841762 and ORCHESTRA, NCT 02081690	Validation of quality-of-life questionnaire
REPAIR, NCT 02310672	Right-ventricle remodeling
RUBATO, NCT 03153137	Fontan circulation
MELODY, NCT 02070991	Combined pre- and postcapillary pulmonary hypertension
TRITON, NCT 02558231	Macitentan and tadalafil in upfront combination versus macitentan, tadalafil, and selexipag in upfront combination

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