OPTIMIZATION OF SPECIFIC THERAPY FOR PULMONARY ARTERIAL HYPERTENSION: THE POSSIBILITIES OF USING ENDOTHELIN RECEPTOR ANTAGONISTS

Modern concepts of pulmonary arterial hypertension (PAH) pathogenesis focus on the key role of endothelial dysfunction of pulmonary vessels. To control the activation of endothelin-1 system, endothelin receptor antagonists (ERA) are current ly used. Until recently, this class of drugs in our country and abroad was represented by two drugs: the sulfonamide derivative - a nonselective ERA bosentan and a non-sulfonamide derivative - ambrisentan, which blocks only ETA-receptors. Not the selectivity of ERAs, but their pharmacokinetic characteristics determine the differences in the profile of efficacy and safety. In 2015, in our country there appeared a new dual antagonist macitentan, which was created to optimize the tissue effects by increasing lipophilicity. In randomized SERAPHIN study, the use of macitental 10 mg compared with placebo contributed to a reduction of the risk of morbidity and mortality in patients with PAH by 45%, and the effect of therapy was not dependent on whether the patients received concomitant specific therapy with inhibitors of phosphodiesterase type 5, oral or inhaled prostanoids. In the paper there summarized indications for prescribing ERA, the data of the evidence base, as well as the concept of switching to optimize the ERA treatment. It is important to emphasize that in case of a satisfactory clinical response with ERA therapy, correction of therapy seems discrete. In the European guidelines 2015, this issue is not considered as having no extensive evidence base. On the other hand, it cannot be ruled out that the use of generic bosentan may lead to a decrease in the treatment effecacy and to provoke the clinical deterioration. At present clinical data intensively accumulate in favor of the strategy of switching from bosentan or ambrisentan to macitentan in PAH patients. It is necessary to assess the potential benefits associated with ERA switching to macitentan, in comparison with the possibilities of combination therapy.

pulmonary arterial hypertension, endothelin receptor antagonists, bosentan, ambrisentan, macitentan, switching strategy

1. Martyniuk TV, Nakonechnikov SN, Chazova I.Ye. Modern approaches to the treatment of patients with pulmonary hypertension in the light of the recommendations of the European Society of Cardiology. Consilium Medicum 2005; 11:957-962. [in Russian]

2. Chazova IYe, Avdeev SN, Tsareva NA, etc. Clinical recommendations on the diagnosis and treatment of pulmonary hypertension. Therapeutic archive. 2014; 9:4–23. [in Russian]

3. Chazova IYe, Martynyuk TV, Nakonechnikov SN Antagonists of endothelium receptors in pulmonary arterial hypertension: yesterday, today and tomorrow. Russian Journal of Cardiology. 2009; 4:73-81. [in Russian]

4. Andreeva Yu.A., Martynyuk T.V., Ataullakhanova D.M. et al. Clinical case: application of a selective antagonist of endothelin receptors ambrisent for idiopathic pulmonary hypertension. Systemic Hypertension. 2008; 1: 57-60. [in Russian]

5. Galiè 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 2016; 37(1): 67-119.

6. Galie N., Manes A., Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004; 61:227–237.

7. Luscher T.F., Wenzel R.R. Endothelin and endothelin antagonists: pharmacology and clinical implications. Agents Actions Suppl 1995; 45: 237–253.

8. Wagner O.F., Christ G., Wojta J. et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem. 1992; 267: 16066–16068.

9. Chazova I.Ye., Martynyuk T.V., Masenko V.P. The role of the lungs in the metabolism of some markers of endothelial damage in norm and with primary pulmonary hypertension. Kardiologiia. 2000; 8: 13-15. [in Russian]

10. Clozel M., Gray G.A. Are there different ETB receptors mediating constriction and relaxation? J Cardiovasc Pharmacol. 1995; 26 (Suppl 3): S262–S264.

11. 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; 327:736–745.

12. Raja S.G. Macitentan: a tissue-targeting endothelin receptor antagonist for the potential oral treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. Curr Opin Investig Drugs. 2010; 11:1066–1073.

13. Martyniuk T.V., Arkhipova O.A., Kobal E.A. et al. The use of a non-selective antagonist of bosentan endothelin receptors in patients with idiopathic pulmonary hypertension: the first Russian experience and a look into the future. Systemic Hypertension. 2011; 4: 51-57. [in Russian]

14. Taichman D.B., Ornelas J., Chung L. et al. Pharmacologic therapy for Pulmonary Arterial Hypertension in Adults CHEST Guideline and Expert Panel Report. CHEST. 2014; 146 (2): 449-475.

15. Galie N., Rubin L.J., Jansa P. et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomized, controlled trial. Lancet. 2008; 371: 2093–2100.

16. Martyniuk T.V., Nakonechnikov S.N., Chazova I.Ye. Ambrisentan: the possibility of treating pulmonary arterial hypertension with the help of selective blockade of the endothelin system. Eurasian heart journal. 2014; 1: 95-108. [in Russian]

17. Rubin L.J., Galie N., Badesch D.B. et al. Ambrisentan improves exercise capacity and clinical measures in pulmonary arterial hypertension. Am J Crit Care Med2004; 169:A210.

18. Olschewski H., Galie N., Ghofrani H. et al. Ambrisentan improves exercise capacity and time to clinical worsening in patients with pulmonary arterial hypertension: Results of the ARIES-2 study. Proc Am Thorac Soc 2006; 3:A728.

19. Pulido T., Adzerikho I., Channick R.N. et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369: 865-866.

20. Burgess, G., Hoogkamer H, Collings L, et al., Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008; 64(1): 43-50.

21. Tracleer EU Summary of Product Characteristics (SPC). Actelion Pharmaceuticals Ltd. February 2016; Available from: http://www.actelion.com/documents/corporate/smpc-pils/tracleer-smpc.pdf.

22. Paul, G.A., Gibbs JS, Boobis AR, et al., Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol. 2005; 60(1): 107-12.

23. J Ohnesorge, B.E., N Benjamin, C Fischer, et al. Change of sildenafil plasma concentrations after transition from bosentan to macitentan in pulmonary arterial hypertension. Pneumologie. 2016; 37(1): 567.

24. Sidharta P.N., M. van Gibersbergen, M. Wolzt, et al. Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects. Br J Clin Pharmacol. 2014; 78(5): 1035-42.

25. 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.

26. 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.

27. Tahara, N., Dobashi H, Fukuda K, et al., Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension. Circ J. 2016; 80(6): 1478-83.

28. Gray C., Jones S., Stewart J. Switch From Bosentan to Macitentan in Patients With Pulmonary Arterial Hypertension. Chest. 2015; 148 (943A).

29. Blok IM, Schuuring MJ., A.Van Dijk, Bet al. New Treatment Opportunities in Pulmonary Hypertension and Congenital Heart Disease. JACC. 2015; 65:10S.

30. Blok IM, Riel A, A. van Dijk, et al. From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement? Intern J Cardiol. 2017; 227: 51-52.