Skip to main content
SpringerLink
Log in

Pharmacokinetic–Pharmacodynamic Relationships of Macitentan, a New Endothelin Receptor Antagonist, After Multiple Dosing in Healthy Korean Subjects

  • Original Research Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Background and objectives

Macitentan is a novel dual endothelin (ET)-1 receptor antagonist to be used in patients with pulmonary arterial hypertension. This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan after administration of multiple doses to healthy Korean male subjects.

Methods

A randomized, double-blind, placebo-controlled, multiple-ascending dose study was performed in 30 healthy male subjects receiving oral macitentan (3, 10, or 30 mg) or placebo once daily for 10 days. Plasma concentrations of macitentan, its active metabolite ACT-13277, and ET-1 were evaluated. Safety and tolerability measurements were conducted throughout the study.

Results

The concentration–time profile of macitentan was characterized by slow absorption (median time to maximum plasma concentration [t max] 9–10 h) and slow elimination (mean elimination half-life [t ½] 11–15 h). After repeated doses of 3, 10, and 30 mg of macitentan over the course of 10 days, the peak concentration (C max) increased as the dose increased and the area under the plasma concentration–time curve during the dosing interval (AUC τ ) increased in a dose-proportional manner. Plasma concentrations showed approximately 1.5- to 1.9-fold accumulation on day 10 compared with day 1. ACT-132577 showed higher levels of exposure than macitentan, its mean half-life was 46–48 h, and it accumulated 7- to 12-fold. Macitentan increased plasma ET-1 concentrations at all doses tested and was well tolerated and elicited no serious adverse events.

Conclusion

Multiple oral doses of 3, 10, and 30 mg of macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Reference

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

    Article  PubMed  Google Scholar 

  2. Webb DJ. Endothelin: from molecule to man. Br J Clin Pharmacol. 1997;44(1):9–20.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.

    Article  PubMed  CAS  Google Scholar 

  4. Anderson JR, Nawarskas JJ. Pharmacotherapeutic management of pulmonary arterial hypertension. Cardiol Rev. 2010;18(3):148–62.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. Benigni A, Remuzzi G. Endothelin antagonists. Lancet. 1999;353(9147):133–8.

    Article  PubMed  CAS  Google Scholar 

  7. Dhaun N, Goddard J, Kohan DE, Pollock DM, Schiffrin EL, Webb DJ. Role of endothelin-1 in clinical hypertension: 20 years on. Hypertension. 2008;52(3):452–9.

    Article  PubMed  CAS  Google Scholar 

  8. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001;69(4):223–31.

    Article  PubMed  CAS  Google Scholar 

  9. Don GW, Joseph F, Celermajer DS, Corte TJ. Ironic case of hepatic dysfunction following the global withdrawal of sitaxentan. Intern Med J. 2012;42(12):1351–4.

    Article  PubMed  CAS  Google Scholar 

  10. Galie N, Hoeper MM, Gibbs JS, Simonneau G. Liver toxicity of sitaxentan in pulmonary arterial hypertension. Eur Respir J. 2011;37(2):475–6.

    Article  PubMed  CAS  Google Scholar 

  11. Trow TK, Taichman DB. Endothelin receptor blockade in the management of pulmonary arterial hypertension: selective and dual antagonism. Respir Med. 2009;103(7):951–62.

    Article  PubMed  Google Scholar 

  12. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Sidharta PN, van Giersbergen PL, 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 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Dingemanse J, Sidharta PN, Maddrey WC, Rubin LJ, Mickail H. 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.

  19. World Medical Association Declaration of Helsinki—ethical principles for medical research involving human subjects. http://www.wma.net/en/30publications/10policies/b3/indexhtml. Accessed 03 July 2013.

  20. European Medicines Agency. ICH Topic E 6 (R1): guideline for good clinical practice. Note for guidance on good clinical practice. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf. Accessed 03 July 2013.

  21. Kummer O, Haschke M, Hammann F, Bodmer M, Bruderer S, Regnault Y, et al. Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan. Eur J Pharm Sci. 2009;38(4):384–8.

    Article  PubMed  CAS  Google Scholar 

  22. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000;17(10):1278–83.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. Bruderer S, Aanismaa P, Homery MC, Hausler S, Landskroner K, Sidharta PN, 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  PubMed  CAS  PubMed Central  Google Scholar 

  25. Gabler NB, French B, Strom BL, Liu Z, Palevsky HI, Taichman DB, et al. Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest. 2012;141(1):20–6.

    Article  PubMed  CAS  Google Scholar 

  26. Loffler BM, Breu V, Clozel M. Effect of different endothelin receptor antagonists and of the novel non-peptide antagonist Ro 46-2005 on endothelin levels in rat plasma. FEBS Lett. 1993;333(1–2):108–10.

    Article  PubMed  CAS  Google Scholar 

  27. Kiowski W, Sutsch G, Hunziker P, Muller P, Kim J, Oechslin E, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet. 1995;346(8977):732–6.

    Article  PubMed  CAS  Google Scholar 

  28. Weber C, Schmitt R, Birnboeck H, Hopfgartner G, van Marle SP, Peeters PA, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther. 1996;60(2):124–37.

    Article  PubMed  CAS  Google Scholar 

  29. Perez-Urizar J, Granados-Soto V, Flores-Murrieta FJ, Castaneda-Hernandez G. Pharmacokinetic–pharmacodynamic modeling: why? Arch Med Res. 2000;31(6):539–45.

    Article  PubMed  CAS  Google Scholar 

  30. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. FDA guidance for industry exposure–response relationships: study design, data analysis, and regulatory applications [online]. 2003 April. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072109.pdf.

  31. Dingemanse J, Gunawardena KA, van Giersbergen PL. Comparison of the pharmacokinetics, pharmacodynamics and tolerability of tezosentan between Caucasian and Japanese subjects. Br J Clin Pharmacol. 2006;61(4):405–13.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

Download references

Acknowledgments

Sponsored by Actelion Pharmaceuticals Ltd, Korea, this study was designed and performed by qualified investigators of the Department of Clinical Pharmacology and Therapeutics of SNUH. Li Young Ahn, Sung Eun Kim, and SoJeong Yi received training program grants from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Korea (A070001, Korea National Enterprise for Clinical Trials).

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea

    Li Young Ahn, Sung Eun Kim, SoJeong Yi, Kyoung Soo Lim, In-Jin Jang & Kyung-Sang Yu

  2. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

    Jasper Dingemanse

Authors
  1. Li Young Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sung Eun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. SoJeong Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jasper Dingemanse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyoung Soo Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. In-Jin Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kyung-Sang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyung-Sang Yu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ahn, L.Y., Kim, S.E., 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 14, 377–385 (2014). https://doi.org/10.1007/s40256-014-0081-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-014-0081-4

Keywords

Search

Navigation