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Macitentan: A Review of Its Use in Patients with Pulmonary Arterial Hypertension

Drugs volume 74, pages 1495–1507 (2014)Cite this article

Abstract

Macitentan (Opsumit®) is an orally active, dual endothelin receptor antagonist (ERA) with tissue targeting properties. Macitentan was approved recently in the EU (as monotherapy or combination therapy) for the long-term treatment of pulmonary arterial hypertension (PAH) in adults of WHO functional class II or III, and in the USA for the treatment of PAH (WHO group I) to delay disease progression and reduce hospitalization for PAH. This article reviews the pharmacological properties, efficacy and tolerability data relevant to the use of macitentan in this indication. Treatment with macitentan 10 mg once daily significantly reduced the risk for the primary composite endpoint of morbidity and mortality in patients with PAH (mostly WHO functional class II or III) in the large, randomized, placebo-controlled SERAPHIN study. Other efficacy outcomes, including exercise capacity, haemodynamic parameters and health-related quality of life also improved significantly with macitentan relative to placebo. Macitentan was generally well tolerated in this study. As with other ERAs, haemoglobin levels decreased with macitentan therapy; however, these were not progressive and stabilized following longer-term treatment. Although comparative studies are needed to definitively position macitentan with respect to other approved agents, current evidence suggests that macitentan is a useful treatment option for initial therapy in patients with WHO functional class II or III PAH, which has the potential advantage of once-daily administration.

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References

  1. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493–537.

    PubMed  Article  Google Scholar 

  2. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S55–66.

    PubMed  Article  Google Scholar 

  3. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–30.

    PubMed  Article  Google Scholar 

  4. Peacock AJ, Murphy NF, McMurray JJ, et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007;30(1):104–9.

    CAS  PubMed  Article  Google Scholar 

  5. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34–41.

    PubMed  Article  Google Scholar 

  6. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):13S–24S.

    CAS  PubMed  Article  Google Scholar 

  7. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S20–31.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. Seferian A, Simonneau G. Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow? Eur Respir Rev. 2013;22(129):217–26.

    PubMed  Article  Google Scholar 

  9. Price LC, Howard LS. Endothelin receptor antagonists for pulmonary arterial hypertension: rationale and place in therapy. Am J Cardiovasc Drugs. 2008;8(3):171–85.

    CAS  PubMed  Article  Google Scholar 

  10. Sparacino-Watkins CE, Lai YC, Gladwin MT. Nitrate-nitrite-nitric oxide pathway in pulmonary arterial hypertension therapeutics. Circulation. 2012;125(23):2824–6.

    PubMed  Article  Google Scholar 

  11. Rubin LJ. Endothelin receptor antagonists for the treatment of pulmonary artery hypertension. Life Sci. 2012;91(13–14):517–21.

    CAS  PubMed  Article  Google Scholar 

  12. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328(24):1732–9.

    CAS  PubMed  Article  Google Scholar 

  13. Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med. 1991;114(6):464–9.

    CAS  PubMed  Article  Google Scholar 

  14. Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004;61(2):227–37.

    CAS  PubMed  Article  Google Scholar 

  15. Sitbon O, Morrell N. Pathways in pulmonary arterial hypertension: the future is here. Eur Respir Rev. 2012;21(126):321–7.

    PubMed  Article  Google Scholar 

  16. European Medicines Agency. Opsumit (macitentan): summary of product characteristics. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002697/WC500160899.pdf. Accessed 16 June 2014.

  17. Actelion Pharmaceuticals US Inc. Opsumit (macitentan): US prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204410s000lbl.pdf. Accessed 16 June 2014.

  18. Bolli MH, Boss C, Binkert C, et al. The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-p ropylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012;55(17):7849–61.

    CAS  PubMed  Article  Google Scholar 

  19. US Center for Drug Evaluation and Reasearch. Macitentan: pharmacology review(s). 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf. Accessed 16 June 2014.

  20. Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736–45.

    CAS  PubMed  Article  Google Scholar 

  21. Gatfield J, Mueller Grandjean C, Sasse T, 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.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. Dingemanse J, Sidharta PN, Maddrey WC, et al. Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf. 2014;13(3):391–405.

    CAS  PubMed  Article  Google Scholar 

  23. Iglarz M, Bossu A, Wanner D, et al. Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension. Life Sci. 2014. doi:10.1016/j.lfs.2014.02.018.

    PubMed  Google Scholar 

  24. Iglarz M, Landskroner K, Rey M, et al. Optimization of tissue targeting properties of macitentan, a new endothelin receptor antagonist, improves its efficacy in a model of pulmonary fibrosis associated with pulmonary arterial hypertension [abstract no. P2506]. Eur Heart J. 2011;32(Suppl 1):434.

    Google Scholar 

  25. Sidharta PN, van Giersbergen PLM, Halabi A, et al. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977–84.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  26. Sidharta PN, van Giersbergen PLM, Dingemanse J. 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.

    PubMed  Google Scholar 

  27. US Center for Drug Evaluation and Reasearch. Macitentan: clinical pharmacology and biopharmaceutics review(s). 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf. Accessed 16 June 2014.

  28. Zisowsky J, Sidharta PN, Krause A, et al. Pharmacokinetic/pharmacodynamic analyses in SERAPHIN, a randomized, controlled study of macitentan in patients with pulmonary arterial hypertension [abstract no. 1709290]. Clin Pharmacol Drug Dev. 2013;2(Suppl 1):29.

    Google Scholar 

  29. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.

    CAS  PubMed  Article  Google Scholar 

  30. Bruderer S, Hopfgartner G, Seiberling M, et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012;42(9):901–10.

    CAS  PubMed  Article  Google Scholar 

  31. Bruderer S, Marjason J, Sidharta PN, et al. Pharmacokinetics of macitentan in Caucasian and Japanese subjects: the influence of ethnicity and sex. Pharmacology. 2013;91(5–6):331–8.

    CAS  PubMed  Article  Google Scholar 

  32. Sidharta PN, Lindegger N, Ulc I, et al. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. 2013;54(3):291–300.

    Article  Google Scholar 

  33. Treiber A, Aeanismaa P, de Kanter R, et al. Macitentan does not interfere with hepatic bile salt transport. J Pharmacol Exp Ther. 2014. doi:10.1124/jpet.114.214106.

    PubMed  Google Scholar 

  34. Atsmon J, Dingemanse J, Shaikevich D, et al. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet. 2013;52(8):685–92.

    CAS  PubMed  Article  Google Scholar 

  35. Bruderer S, Äänismaa P, Homery M-C, et al. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14(1):68–78.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. Sidharta P, van Giersbergen P, Wolzt M, et al. Lack of clinically relevant pharmacokinetic interactions between the dual endothelin receptor antagonist macitentan and sildenafil in healthy subjects [abstract]. Am J Respir Crit Care Med. 2012;185:A4802.

    Google Scholar 

  37. Sidharta PN, Dietrich H, Dingemanse J. Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Clin Drug Investig. 2014. doi:10.1007/s40261-014-0207-0.

    PubMed  Google Scholar 

  38. Channick RN, Delcroix M, Galie N, et al. Reduction of pulmonary arterial hypertension (PAH)-related hospitalizations with macitentan in the randomized controlled trial seraphin [abstract no. PRS4]. Value Health. 2013;16(3):A231.

    Article  Google Scholar 

  39. Jansa P, Channick R, Delcroix M, et al. Impact of macitentan on the health-related quality of life (HRQoL) in pulmonary arterial hypertension (PAH): results from a long-term randomised controlled trial [abstract no. P4075]. Eur Respir J. 2013;42(Suppl 57):862s.

    Google Scholar 

  40. Sitbon O, Channick R, Delcroix M, et al. Effect of macitentan on haemodynamics in SERAPHIN, a randomised controlled trial in pulmonary arterial hypertension (PAH) [abstract no. P4060]. Eur Respir J. 2013;42(Suppl 57):858s.

    Google Scholar 

  41. Mehta S, Delcroix M, Galie N. Macitentan reduced all-cause hospitalization in patients with pulmonary arterial hypertension: data from the randomized controlled SERAPHIN trial [abstract no. A2458]. In: American Thoracic Society proceedings; 16–21 May 2014; San Diego.

  42. Channick R, Delcroix M, Galie N, et al. The effect of macitentan on long-term outcomes in patients with pulmonary arterial hypertension by WHO functional class: data from the randomized controlled SERAPHIN study [abstract no. A4783]. In: American Thoracic Society proceedings; 16–21 May 2014; San Diego.

  43. Simonneau G, Channick R, Delcroix M, et al. Effect of macitentan on long-term outcomes in patients with pulmonary arterial hypertension (PAH): subanalysis of SERAPHIN comparing incident and prevalent patient populations not treated with background PAH-specific therapy [abstract]. Chest. 2013;144(4 Meeting abstracts):876A.

    Article  Google Scholar 

  44. European Medicines Agency. Assessment report: Opsumit (macitentan). 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002697/WC500160900.pdf. Accessed 16 June 2014.

  45. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [erratum appears in Circulation. 2009;120:e13. Circulation. 2009;119(16):2250–94.

    PubMed  Article  Google Scholar 

  46. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60–72.

    PubMed  Article  Google Scholar 

  47. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301.

    CAS  PubMed  Article  Google Scholar 

  48. European Medicines Agency. Volibris (ambrisentan): summary of product characteristics. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000839/WC500053065.pdf. Accessed 16 June 2014.

  49. European Medicines Agency. Tracleer (bosentan): summary of product characteristics. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000401/WC500041597.pdf. Accessed 16 June 2014.

  50. Weiss J, Theile D, Ruppell MA, et al. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013;701(1–3):168–75.

    CAS  PubMed  Article  Google Scholar 

  51. Lepist E-I, Gillies H, Smith W, et al. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. PLoS One. 2014;9(1):e87548.

    PubMed Central  PubMed  Article  Google Scholar 

  52. Clarke M, Walter C, Agarwal R, et al. Macitentan (Opsumit) for the treatment of pulmonary arterial hypertension. Expert Rev Clin Pharmacol. 2014;7(4):415–21.

    CAS  PubMed  Article  Google Scholar 

  53. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S97–107.

    PubMed  Article  Google Scholar 

  54. Actelion. Update on the DUAL program in digital ulcers in systemic sclerosis [media release]. 02 Dec 2013. http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1746886.

  55. Raghu G, Million-Rousseau R, Morganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42(6):1622–32.

    CAS  PubMed  Article  Google Scholar 

  56. Patel T, McKeage K. Macitentan: first global approval. Drugs. 2014;74(1):127–33.

    CAS  PubMed  Article  Google Scholar 

  57. Abe K, Kunita M, Hirooka Y, et al. Long-term treatment with novel endothelin receptor antagonist macitentan markedly attenuated severe pulmonary hypertension with angioproliferative occlusive lesions in rats [abstract]. Am J Respir Crit Care Med. 2013;187:A4632.

    Google Scholar 

  58. Sidharta PN, Lindegger N, Reseski K, et al. Macitentan, a novel dual endothelin receptor antagonist, does not prolong the QT/QTc interval in a thorough QTc study in healthy subjects [abstract no. PIII-61]. Clin Pharmacol Ther. 2013;93(Suppl 1):S108–9.

    Google Scholar 

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Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Sohita Dhillon is a salaried employee of Adis/Springer.

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    Sohita Dhillon

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Correspondence to Sohita Dhillon.

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The manuscript was reviewed by: N. Galie, Institute of Cardiology, University of Bologna, Bologna, Italy; L.J. Rubin, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Diego School of Medicine, La Jolla (CA), USA.

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Dhillon, S. Macitentan: A Review of Its Use in Patients with Pulmonary Arterial Hypertension. Drugs 74, 1495–1507 (2014). https://doi.org/10.1007/s40265-014-0266-9

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Keywords

  • Pulmonary Arterial Hypertension
  • Idiopathic Pulmonary Fibrosis
  • Functional Class
  • Bosentan
  • PDE5 Inhibitor