Skip to main content
SpringerLink
Log in

Macitentan: A Review in Pulmonary Arterial Hypertension

  • Adis Drug Evaluation
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Macitentan (Opsumit®) is an orally active, potent, dual endothelin (ET) receptor antagonist that is indicated for the treatment of pulmonary arterial hypertension (PAH). In the pivotal SERAPHIN trial in patients aged ≥12 years with PAH, the risk of first PAH-related event or all-cause death (primary composite endpoint) was significantly reduced by 45 % with oral macitentan 10 mg once daily versus placebo. Macitentan significantly reduced the risk of the primary composite endpoint across various patient subgroups. The risk of all-cause hospitalization and PAH-related hospitalization was also significantly reduced by macitentan, according to post hoc analysis. Macitentan was generally well tolerated in SERAPHIN. In conclusion, macitentan is an important option for the treatment of PAH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl D):D42–50.

    Article  PubMed  Google Scholar 

  2. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336(2):111–7.

    Article  CAS  PubMed  Google Scholar 

  3. Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67–119.

    Article  PubMed  Google Scholar 

  4. Hoeper MM, McLaughlin VV, Dalaan AM, et al. Treatment of pulmonary hypertension. Lancet Respir Med. 2016;4(4):323–6.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Actelion Pharmaceuticals US Inc. Opsumit® (macitentan) tablets, for oral use: US prescribing information. 2016. http://opsumit.com/. Accessed 8 Aug 2016.

  9. European Medicines Agency. Opsumit (macitentan): EU summary of product characteristics. 2016. http://www.ema.europa.eu/. Accessed 8 Aug 2016.

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012;55(17):7849–61.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shinohara T, Sawada H, Otsuki S, et al. Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis. Am J Physiol Lung Cell Mol Physiol. 2015;308(6):L523–38.

    Article  CAS  PubMed  Google Scholar 

  14. Iglarz M, Landskroner K, Bauer Y, et al. Comparison of macitentan and bosentan on right ventricular remodeling in a rat model of non-vasoreactive pulmonary hypertension. J Cardiovasc Pharmacol. 2015;66(5):457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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;118(2):333–9.

    Article  CAS  PubMed  Google Scholar 

  16. 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. 3863 plus poster]. Eur Respir J. 2013;42(Suppl 57):P4060.

    Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Lindegger N, Sidharta PN, Reseski K, et al. Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects. Pulm Pharmacol Ther. 2014;29(1):41–8.

    Article  CAS  PubMed  Google Scholar 

  19. de Kanter R, Sidharta PN, Delahaye S, et al. Physiologically-based pharmacokinetic modeling of macitentan: prediction of drug-drug interactions. Clin Pharmacokinet. 2016;55(3):369–80.

    Article  PubMed  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Ahn LY, Kim SE, Yi S, et al. Pharmacokinetic-pharmacodynamic relationships of macitentan, a new endothelin receptor antagonist, after multiple dosing in healthy Korean subjects. Am J Cardiovasc Drugs. 2014;14(5):377–85.

    Article  CAS  PubMed  Google Scholar 

  24. Sidharta PN, Lindegger N, Ulč I, et al. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. 2014;54(3):291–300.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Hurst N, Pellek M, Dingemanse J, et al. Lack of pharmacokinetic interactions between macitentan and a combined oral contraceptive in healthy female subjects. J Clin Pharmacol. 2016;56(6):669–74.

    Article  CAS  PubMed  Google Scholar 

  28. Sidharta PN, van Giersbergen PLM, 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 

  29. 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;34(8):545–52.

    Article  CAS  PubMed  Google Scholar 

  30. Treiber A, Äänismaa P, de Kanter R, et al. Macitentan does not interfere with hepatic bile salt transport. J Pharmacol Exp Ther. 2014;350(1):130–43.

    Article  PubMed  Google Scholar 

  31. Channick RN, Delcroix M, Ghofrani H-A, et al. Effect of macitentan on hospitalizations: results from the SERAPHIN trial. JACC Heart Fail. 2015;3(1):1–8.

    Article  PubMed  Google Scholar 

  32. Channick RN, 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. C93 plus poster]. Am J Respir Crit Care Med. 2014;189:A4783.

    Google Scholar 

  33. Galie N, Delcroix M, Ghofrani H-A, et al. Anticoagulant therapy does not influence long-term outcomes in patients with pulmonary arterial hypertension (PAH): insights from the randomised controlled SERAPHIN trial of macitentan [abstract no. 65]. Eur Heart J. 2014;35(Suppl 1):10.

    Google Scholar 

  34. Sitbon O, Channick RN, Delcroix M, et al. Macitentan reduces the risk of morbidity and mortality irrespective of the presence or absence of right ventricular (RV) impairment: results from the randomised SERAPHIN trial in pulmonary arterial hypertension (PAH) [abstract]. Eur Respir J. 2014;44(Suppl 58):3419.

    Google Scholar 

  35. Simonneau G, Channick RN, Delcroix M, et al. Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN. Eur Respir J. 2015;46(6):1711–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Youssef P, Galie N, Perchenet L, et al. Effect of macitentan on health-related quality of life (HRQOL) in pulmonary arterial hypertension (PAH): results from the SERAPHIN randomised controlled trial [abstract no. ARA-P76]. Intern Med J. 2014;44(Suppl 2):31.

    Google Scholar 

  37. Kim NH, Chin KM, Muros-Le Rouzic E, et al. OPsumit® USers Registry (OPUS): insights into the safety and tolerability of Opsumit® [abstract no. P1031 plus poster]. Am J Respir Crit Care Med. 2016;193:A7396.

    Google Scholar 

  38. Safdar Z, Thakur A, Frost A. Edema in patient switched to macitentan from bosentan and ambrisentan in pulmonary arterial hypertension [abstract]. Chest. 2015;148(4):939A–B.

  39. Blok IM, Van Riel ACMJ, Schuuring MJ, et al. Macitentan superior to bosentan in pulmonary arterial hypertension due to congenital heart disease? [abstract no. P2658]. Eur Heart J. 2015;36(Suppl 1):458.

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  41. Aversa M, Porter S, Granton J. Comparative safety and tolerability of endothelin receptor antagonists in pulmonary arterial hypertension. Drug Saf. 2015;38(5):419–35.

    Article  CAS  PubMed  Google Scholar 

  42. Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834–44.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

During the peer review process, the manufacturer of macitentan was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand

    Gillian M. Keating

Authors
  1. Gillian M. Keating
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gillian M. Keating.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

Gillian Keating is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

The manuscript was reviewed by: I. M. Lang, Department of Internal Medicine II, Division of Cardiology, AKH-Vienna, Medical University of Vienna, Vienna, Austria; 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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Keating, G.M. Macitentan: A Review in Pulmonary Arterial Hypertension. Am J Cardiovasc Drugs 16, 453–460 (2016). https://doi.org/10.1007/s40256-016-0188-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-016-0188-x

Keywords

Search

Navigation