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Macitentan: A New Endothelin Receptor A/B Blocker for Treatment of Pulmonary Arterial Hypertension.

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Overview

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Macitentan (OPSUMIT; Figure 1) is a nonselective endothelin receptor antagonist (ERA) that was FDA-approved in October 2013 for the treatment of pulmonary arterial hypertension (PAH). 1,2 The clinical approval of macitentan was based on data from the long-term SERAPHIN study, which established the safety and effectiveness of the drug in patients suffering from PAH.1,3 A once-daily 10 mg oral dose of macitentan was shown to delay disease progression of PAH and reduce the risk of morbidity and mortality by 45%.3 Macitentan is generally well tolerated; most common adverse effects include nasopharyngitis, headache and anemia.2,3 Compared to other ERAs, macitentan exhibits a significantly slower receptor-dissociation rate that may afford it better efficacy.2,4  Like other ERAs, macitentan may be harmful to a developing fetus and thus carries a boxed warning for pregnant women. The drug may only be given to female patients of reproductive age through the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) program.1,2

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Mechanism of Action

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Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen. The levels of ET-1 are upregulated in PAH and correlate with the pathophysiology of the disease.5 ET-1 exerts its effects through two types of receptors: the endothelin-A receptor (ETAR) and the endothelin-B receptor (ETBR). Macitentan is a nonselective endothelin receptor antagonist (ERA) that blocks the binding of ET-1 to both ETA and ETB receptors.4,6,7 In pulmonary arterial smooth muscle cells, macitentan was shown to be as potent as other ERAs (bosentan and ambrisentan) in inhibiting ET-1 induced Ca++ release; however, macitentan displayed slow and insurmountable receptor dissociation kinetics compared to the competitive kinetics of bosentan and ambrisentan (receptor occupancy half-life (ROt1/2): ~17 minutes for macitentan; ~70 sec for bosentan; and ~40 sec for ambrisentan).4 The high affinity and sustained inhibitory characteristics of macitentan are suggested to offer improved clinical efficacy compared to the other ERAs.2,4

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Background and Clinical Pharmacology

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Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance, vascular proliferation and remodeling, which may progress to right heart failure and death. Patients experience shortness of breath, fatigue due to right heart failure and severe restrictions of exercise capabilities. Treatments aim to decrease pulmonary vascular resistance and improve exercise capacity. Increased levels of ET-1 and decreased levels of vasodilators such as NO and PGI2 contribute to the pathophysiology of PAH.8  Current treatments approved for PAH include ERAs, PDE5 inhibitors, and prostacyclin (PGI2) and its analogs.8

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The pathophysiological role of ET-1 is established in PAH. Macitentan prevents ET-1-induced pulmonary vasoconstriction by blocking ETA and ETB receptors. The approval of macitentan was based on the results of the large, randomized and long-term (up to 3.5 years; median 2 years) SERAPHIN study (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) aimed to evaluate the safety and efficacy of macitentan using the primary end point of morbidity and mortality.3 A total of 742 patients diagnosed with PAH were randomly assigned in a 1:1:1 ratio to receive once-daily placebo; once-daily 3 mg macitentan; or once-daily 10 mg macitentan.3 The primary end point was defined as the time to the occurrence of the first event related to PAH which included: worsening of PAH (defined by worsening of symptoms of PAH, a decrease in 6-minute walk by at least 15% from baseline, and the need for additional treatment); initiation of treatment with prostanoids; lung transplantation; atrial septostomy or death.3 Secondary end points included change from baseline by month 6 in the 6-minute walk distance and WHO functional class; hospitalization or death due to PAH up to the end of the treatment; and death from any cause up to the end of the study.3

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Compared to placebo group, macitentan treatment reduced the risk of morbidity and mortality by 45% (p<0.0001) for patients receiving the 10 mg dose and by 30% (p=0.0108) for patients receiving the 3 mg dose. A primary end point was reported in 46% of subjects in the placebo group, 38% in the 3 mg macitentan group, and 31% in the 10 mg macitentan group.2,3 Death or hospitalization due to PAH was 34% of subjects in the placebo group, 26% in the 3 mg macitentan, and 21% in the 10 mg macitentan group. By 6 months, patients on macitentan showed significant improvement in the 6-minute walk distance (+7.4 m with 3 mg macitentan; +12.5 m with 10 mg macitentan), while patients in the placebo group exhibited a decrease (-9.4 m) in the 6-minute walk distance.2,3

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Pharmacokinetics

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The recommended macitentan dose is a 10 mg tablet, administered orally once a day.2,9 Peak plasma concentrations are achieved within 8 hours post-dose. Bioavailability is not affected by food.  Macitentan is metabolized by oxidative depropylation of the sulfamide (mainly by CYP3A4 and some CYP2C19) into its active metabolite ACT-132577. Macitentan and its active metabolite ACT-132577 are > 99% bound to plasma proteins, mainly albumin. The half-lives of macitentan and ACT-132577 are:~16 hours and 48 hours, respectively. At steady state, the plasma levels of the active metabolite are 3X those of macitentan and may contribute to  ~40% of the pharmacological activity. Excretion of macitentan is mostly in the form of non-active metabolites of which ~50% are recovered in urine and ~25% in feces.2,10 No dose adjustments are necessary for patients with renal or hepatic impairments.11 Rifampin, a strong inducer of CYP3A4, decreases the plasma concentration of macitentan by 79%; while ketoconazole, a CYP3A4 inhibitor, doubles the levels of macitentan.2,12

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Adverse Effects

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Most commonly reported adverse effects include anemia (13.2% with macitentan vs. 3.2% in placebo group), nasopharyngitis (14% with macitentan vs. 10.4% in placebo), sore throat, bronchitis (11.6% with macitentan vs. 5.6% in placebo), and headache.2,3 All available ERAs can cause elevation of aminotransferases and hepatotoxicity. In the SERAPHIN study, there were no significant differences in the incidence of elevated aminotransferases (3X upper limit of normal (ULN) range) between macitentan treatment and the placebo group;3 however, it is recommended that health care providers measure liver enzymes levels before initiation and during macitentan treatment.2

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Macitentan may cause serious embryo-fetal toxicity and thus carries a Boxed Warning against use in pregnant women. Female patients of reproductive age can only receive macitentan through the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS).1,2 In males, the drug may reduce sperm count and affect fertility.

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(NOTE TO REVIEWER - the update texted contained no "(Fig 1)" - I created a link so you could see how the figure is showing up. Please add where you would like the figure link. Thanks - JB)

Reference(s) +
 3. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hyeprtension. N Eng J Med. 2013; 369:809-818 (2013).
 4. Gatfield J et al. Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells. PLoS One. 2012; 7(10):e47662.
 5. Abman SH. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annu Rev Med. 2009; 60:13-23.
 6. Weiss J et al. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013; 701:168-75
 7. Iglarz M et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736-45.
 8. Barnes PJ. Chapter 36. Pulmonary Pharmacology. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12e. New York: McGraw-Hill; 2011. http://accessmedicine.mhmedical.com/content.aspx?bookid=374&sectionid=41266244.
 9. Sidharta PN et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol. 2013. 53(11):1131-8. doi: 10.1002/jcph.152. Epub 2013 Sep 4.
10. Bruderer S et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012;42(9):901-10.   [PubMed: 22458347]
11. Sidharta PN et al. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. 2013 Oct 3. doi: 10.1002/jcph.193.   [PubMed: 24122797]
12. Bruderer S et al. Effect of cyclosporine A and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14(1):68-78.   [PubMed: 22189899]

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Graphic Jump Location

Figure 1: Chemical Structure of Macitentan (also known as: ACT-064992, ACT064992, HY-14184, 441798-33-0).IUPAC Name: 5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine.  PubChem CID 16004692.

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