The place of tadalafil in the treatment of PAH in the light of new clinical guidelines of the Eurasian Association of Cardiologists

Pulmonaryarterialhypertension(PAH)isalife-threateningcardiovascular disease that is characterized by a marked increase in pulmonary vascular resistance and pulmonary artery pressure due to obstructive remodeling of the pulmonary vascular bed with the development of right ventricular heart failure as a cause of premature mortality. Impaired synthesis and reduced bioavailability of nitric oxide is one of the key pathophysiological mechanisms of the development and progression of the disease. The review paper presents key data from the evidence base on the clinical use of tadalafil, a phosphodiesterase type 5 inhibitor (PDE5), which in August 2023 approved by the Pharmaceutical Committee of the Russian Ministry of Health for the indication – treatment of patients with PAH. Tadacardil from Canonpharma Production is the first and only drug in Russian practice today with the active substance tadalafil with the registered indication “PAH”, approved in the Eurasian Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 and available on the territory of the Russian Federation and the EAEU. Tadacardil is indicated for use in adult patients with PAH functional class II and III according to the WHO classification to increase exercise tolerance. The efficacy of tadalafil has been shown in idiopathic PAH and PAH associated with connective tissue diseases. The recommended dose is 40 mg (2 tablets of 20 mg) once a day. The paper describes the mechanism of action and pharmacological effects of PDE5 inhibitors, features of the pharmacokinetics of tadalafil in comparison with other drugs of the class. The advantages of Tadacardil from Canonpharma Production are the proven effecacy of use in patients with PAH, ease of use due to a single dose of 2 tablets of 20 mg once a day in a standard dose; good tolerability and favorable safety profile; proven bioequivalence to the reference drug. In light of the new Eurasian recommendations for the diagnosis and treatment of PH, tadalafil has a wide field for clinical use, which will improve the treatment options for patients with PAH both in mono- and combination therapy.

1. Martynyuk T.V. Pulmonary hypertension: diagnosis and treatment. Moscow, 2018. Series Library of the National Medical Research Center of Cardiology. (In Russ.) ISBN 978-5-6040008-0-9

2. Humbert M., Kovacs G., Hoeper M.M., et al. ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Developed by 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 for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). Eur Heart J 2022; 43(38):3618– 3731. https://doi.org/10.1093/eurheartj/ehac237

3. Chazova I.E., Martynyuk T.V. Pulmonary hypertension. – Moscow. Practice. 2015; 928s. (In Russ.) ISBN 978-5-89816-138-5

4. Morrell N.W., Adnot S., Archer S.L. et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:S20– 31. https://doi.org/10.1016/j.jacc.2009.04.018

5. Galie N., Humbert M., Vachiery J.L., et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Respir J 2015;46(4):903-75. https://doi.org/10.1183/13993003.01032-2015

6. Avdeev S.N., Barbarash O.L., Bautin A.E., et al. 2020 Clinical practice guidelines for Pulmonary hypertension, including chronic thromboembolic pulmonary hypertension. Russian Journal of Cardiology. 2021;26(12):4683. (In Russ.) https://doi.org/10.15829/1560-4071-2021-4683

7. Chazova I.E., Martynyuk T.V., Valieva Z.S., Azizov V.A., Barbarash O.L., Veselova T.N., Galyavich A.S., Gorbachevsky S.V., Zelveian P.A., Lazareva I.V., Mukarov M.A., Nakonetchnikov S.N., Saidova M.A., Sarybaev A.Sh., Stukalova O.V., Shalaev S.V., Shmalts A.A. Eurasian clinical guidelines on diagnosis and treatment of pulmonary hypertension. Eurasian heart journal. 2020;(1):78-122. (In Russ.) https://doi.org/10.38109/2225-1685-2020-1-78-122

8. Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214–221. https://doi.org/10.1056/nejm199507273330403

9. Corbin J.D., Francis S.H. Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract 2002;56:453–459. PMID: 12166544

10. Corbin J.D., Beasley A., Blount M.A., Francis S.H. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun. 2005;334:930–938. https://doi.org/10.1016/j.bbrc.2005.06.183

11. Galie N., Ghofrani H.A., Torbicki A., et al. The Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157. https://doi.org/10.1056/nejmoa050010

12. Tadacardil Canon – instructions for use Registration number: LP-No (002922)-(RG-RU) dated 08/02/2023 https://grls.rosminzdrav.ru/; Register of SmPCs and medicinal products of the EAEU No. RU LPNo. (002922)-(RG-RU) 02.08.2023 (In Russ.)

13. Martynyuk T.V. «Phosphodiesterase type 5 inhibitors.» Chapter in the reference book «Rational pharmacotherapy of heart and vascular diseases. Compendium». Ed. of S.A. Boytsov, Yu.A. Karpov. GEOTARMEDIA, Moscow, 2023. pp. 213-254. (In Russ.)

14. Wharton J., Strange J.W., Moller G.M., et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med. 2005;172:105–113. https://doi. org/10.1164/rccm.200411-1587oc

15. Muirhead G.J., Wulff M.B., Fielding A., et al. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol 2000;50:99–107. https://doi.org/10.1046/j.1365-2125.2000.00245.x

16. Garraffo R., Lavrut T., Ferrando S., et al. Effect of tipranavir/ ritonavir combination on the pharmacokinetics of tadalafil in healthy volunteers. J Clin Pharmacol 2011;51:1071–1078. https://doi.org/10.1177/0091270010379808

17. Wrishko R.E, Dingemanse J., Darstein Yu.A., et al. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008;48:610–618. https://doi. org/10.1177/0091270008315315

18. Galiè N., Brundage B.H., Ghofrani H.A., et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894–2903. https://doi.org/10.1161/CIRCULATIONAHA.108.839274

19. Frantz R.P., Durst L., Burger C. D., et al. Conversion from sildenafil to tadalafil: results from the sildenafil to tadalafil in pulmonary arterial hypertension (SITAR) study. J of Сardiovasc. Рharmacol and Тher. 2014;19(6):550–557. https://doi.org/10.1177/1074248414528066

20. Galiè N., Barbera J.A., Frost A.E., et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373:834–844. https://doi.org/10.1056/nejmoa1413687

21. Hoeper M.M., McLaughlin V.V., Barbera J.A., et al. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med 2016;4:894–901. https://doi.org/10.1016/S2213-2600(16)30307-1 22. Sitbon O., Cottin V., Canuet, M., et al. Initial combination therapy of macitentan and tadalafil in pulmonary arterial hypertension. Eur Respir J 2020; 56(3): 2000673. doi: 10.1183/13993003.00673-2020

22. Sitbon O., Sattler C., Bertoletti L, et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J 2016;47(6):1727-36. https://doi.org/10.1183/13993003.02043-2015

23. Chin K.M., Sitbon O., Doelberg M., et al. Three versus two-drug therapy for patients with newly diagnosed pulmonary arterial hypertension. J Am Coll Cardiol 2021;78:1393–1403. https://doi.org/10.1016/j. jacc.2021.07.057

24. Ivy D., Bonnet D., Berger R., et al. Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double-blind placebo-controlled study. Pulm Circ 2021;11:20458940211024955. https://doi.org/10.1177/20458940211024955

25. Small D., Ferguson-Sells L., Dahdah N., et al. Pharmacokinetics and safety of tadalafil in a paediatric population with pulmonary arterial hypertension: a multiple ascending-dose study. Br J Clin Pharmacol 2019; 85:2302–2309. https://doi.org/10.1111/bcp.14039

26. Henrie A, Nawarskas J, Anderson J. Clinical utility of tadalafil in the treatment of pulmonary arterial hypertension: an evidence-based review. Core Evidemce. 2015 Volume 2015;10:99-109, https://doi.org/10.2147/CE.S58457