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Drugs

, Volume 68, Issue 15, pp 2195–2204 | Cite as

Ambrisentan

Adis Drug Profile

Abstract

  • ▴ Elevated endothelin (ET)-1 levels are strongly correlated with the pathogenesis and prognosis of pulmonary arterial hypertension (PAH). Ambrisentan is an orally active, highly selective ETa receptor antagonist with >4000-fold higher selectivity over the ETb receptor.

  • ▴ In two large, well designed, 12-week, placebo-controlled, phase III trials (ARIES-1, n = 202 and ARIES-2, n = 192) in patients with PAH (WHO group I), ambrisentan 2.5–10 mg once daily significantly increased 6-minute walk distance by 31–59 m from baseline (primary outcome measure) versus placebo.

  • ▴ The incidence of clinical worsening (secondary outcome measure) was significantly delayed for the combined ambrisentan 5 mg once daily groups versus the combined placebo groups from ARIES-1 and -2.

  • ▴ At week 12, WHO functional class distribution was significantly improved with once-daily ambrisentan 5 mg, and Borg dyspnoea scores were significantly improved with ambrisentan 2.5–10 mg versus placebo in combined data from the ARIES-1 and -2 trials.

  • ▴ The beneficial effects of ambrisentan on exercise capacity, WHO functional class and Borg dyspnoea scores seen at 12 weeks were maintained at 48 weeks in the ARIES-E phase III extension trial (n = 361). One-year survival rates with ambrisentan were 95–97%.

  • ▴ Treatment with ambrisentan for up to 2.8 years was generally well tolerated in clinical trials.

Keywords

Pulmonary Arterial Hypertension Bosentan Idiopathic Pulmonary Arterial Hypertension Ambrisentan Treprostinil 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements and Disclosures

This manuscript was reviewed by: N. Galiè, Institute of Cardiology, University of Bologna, Bologna, Italy; A. Manes, Institute of Cardiology, University of Bologna, Bologna, Italy.

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 on the basis of scientific and editorial merit.

References

  1. 1.
    Simonneau G, Galie N, Rubin L, et al. Clinical classification of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: S5–12CrossRefGoogle Scholar
  2. 2.
    Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 2007 Jun; 131(6): 1917–28PubMedCrossRefGoogle Scholar
  3. 3.
    Driscoll JA, Chakinala MM. Medical therapy for pulmonary arterial hypertension. Expert Opinion on Pharmacotherapy 2008; 9(1): 65–81PubMedCrossRefGoogle Scholar
  4. 4.
    Galie N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004 Dec; 25(24): 2243–78Google Scholar
  5. 5.
    WHO. The Global Alliance against Chronic Respiratory Diseases. Pulmonary hypertension [online]. Available from URL: http://www.who.int/gard/publications/MtgReport_GM-Seoul_Final.pdf [Accessed 2008 Jul 2]
  6. 6.
    Hoeper MM. Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs 2005; 65(10): 1337–54PubMedCrossRefGoogle Scholar
  7. 7.
    Liu C, Chen J. Endothelin receptor antagonists for pulmonary hypertension. Cochrane Database of Systematic Reviews 2006; (2): CD004434Google Scholar
  8. 8.
    National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical parctice in the UK and Ireland. Heart 2008; 94: 1–41CrossRefGoogle Scholar
  9. 9.
    D’Alonzo G, Barst R, Ayres S, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991; 115: 343–9PubMedGoogle Scholar
  10. 10.
    Channick RN, Sitbon O, Barst RJ, et al. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004 Jun 16; 43 (12 Suppl. S): 62–7SCrossRefGoogle Scholar
  11. 11.
    Kirkby NS, Hadoke PW, Bagnall AJ, et al. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol 2008 Mar; 153(6): 1105–19PubMedCrossRefGoogle Scholar
  12. 12.
    Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008 Feb; 31(2): 407–15PubMedCrossRefGoogle Scholar
  13. 13.
    Croom KF, Curran MP. Sildenafil: a review of its use in pulmonary arterial hypertension. Drugs 2008; 68(3): 383–97PubMedCrossRefGoogle Scholar
  14. 14.
    Oldfield V, Lyseng-Williamson KA. Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. Am J Cardiovasc Drug 2006; 6(3): 189–208CrossRefGoogle Scholar
  15. 15.
    Scott L. Sitaxentan in pulmonary arterial hypertension. Drugs 2007; 67(5): 761–70PubMedCrossRefGoogle Scholar
  16. 16.
    Price LC, Howard LS. Endothelin receptor antagonists for pulmonary arterial hypertension: rationale and place in therapy. Am J Cardiovasc Drugs 2008; 8(3): 171–85PubMedCrossRefGoogle Scholar
  17. 17.
    Gilead Sciences Inc. Letairis (ambrisentan) tablets for oral use [online]. Available from URL: http://www.gilead.com/pdf/letairis [Accessed 2008 Jul 1]
  18. 18.
    Opitz CF, Ewert R, Kirch W, et al. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J 2008; 29(16): 1936–48PubMedCrossRefGoogle Scholar
  19. 19.
    Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 1998; 114: S208–12CrossRefGoogle Scholar
  20. 20.
    FDA. Application number 22-081 [online]. Available from URL: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist [Accessed 2008 Jul 7]
  21. 21.
    Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117: 3010–9PubMedCrossRefGoogle Scholar
  22. 22.
    Leuchte H, Holzapfel M, Baumgartner R, et al. Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol 2004; 43: 764–70PubMedCrossRefGoogle Scholar
  23. 23.
    Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006; 129: 1313–21PubMedCrossRefGoogle Scholar
  24. 24.
    Galie N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005 Aug 2; 46(3): 529–35PubMedCrossRefGoogle Scholar
  25. 25.
    Rubin L, Dufton C, Gerber M. Ambrisentan for pulmonary arterial hypertension. Future Cardiol 2005; 1(4): 425–32PubMedCrossRefGoogle Scholar
  26. 26.
    Gerber MJ, Dufton C, Pentikis H, et al. Ambrisentan has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of warfarin. Chest 2006 Oct 1; 130 Suppl. 4: 256Google Scholar
  27. 27.
    Dufton C, Gerber MJ, Yin O, et al. No clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil. Chest 2006 Oct 1; 130 Suppl. 4: 254Google Scholar
  28. 28.
    Oudiz RJ, ARIES study group. Long-term ambrisentan therapy provides sustained benefit in patients with pulmonary arterial hypertension. Chest 2007 Oct; 132 Suppl. 4: 474Google Scholar
  29. 29.
    Galie N, Keogh A, Frost A, et al. Ambrisentan long-term safety and efficacy in pulmonary arterial hypertension: one year follow-up [abstract no. M14227]. Proc Am Thorac Soc 2005; 2 (Abstr. Suppl.): A299Google Scholar
  30. 30.
    Badesch D, Zwicke D, Keogh AM, et al. Long-term benefits of ambrisentan in patients with pulmonary arterial hypertension associated with connective tissue diseases [abstract]. Arthritis Rheum 2005 Sep; 52 (Suppl. 9): 166Google Scholar
  31. 31.
    Gilead Sciences. ARIES: ambrisentan in patients with moderate to severe pulmonary aterial hypertension (PAH) [ClinicalTrials.gov identifier NCT00091598]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2008 Jun 24]
  32. 32.
    Gilead Sciences. Study of BSF 208075 evaluating exercise capacity in patients with pulmonary arterial hypertension [ClinicalTrials.gov identifier NCT00046319]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2008 Jun 24]
  33. 33.
    Gilead Sciences. A long term study of ambrisentan in pulmonary arterial hypertension subjects having completed AMB-320 or AMB-321 [ClinicalTrials.gov identifier NCT00578786]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2008 Jun 24]
  34. 34.
    Myogen. Phase 2 extension study of ambrisentan in pulmonary arterial hypertension [ClinicalTrials.gov identifier NCT00424021]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2008 Jun 24]
  35. 35.
    Olschewski H, and The Ambrisentan in PAH Study Group. Long-term safety and tolerance of ambrisentan in patients with pulmonary arterial hypertension [abstract no. 1335]. Eur Respir J Suppl 2005 Sep; 26 Suppl. 49: 205Google Scholar
  36. 36.
    McGoon M, Frost A, Rubin L, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxesntan due to liver function abnormalities: 1 year follow-up. Am J Respir Crit Care Med 2007 Apr; 175 Suppl. 4: 301Google Scholar
  37. 37.
    Myogen. Phase 2 study of ambrisentan for liver function test rescue in pulmonary arterial hypertension [ClinicalTrials.gov identifier NCT00423592]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2008 Jun 24]
  38. 38.
    McGoon M, Frost A, Oudiz R, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. Epub 2008 Sep 23Google Scholar
  39. 39.
    European Medicines Agency. Volibris: summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/volibris/H-839-PI-en.pdf [Accessed 2008 Jul 1]

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Wolters Kluwer Health ¦ AdisMairangi Bay, North Shore 0754, AucklandNew Zealand
  2. 2.Wolters Kluwer HealthConshohockenUSA

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