Pediatr Pulmonol. 2021 Dec 17; doi: 10.1002/ppul.25796. Epub 2021 Dec 17.

Safety and tolerability of combination therapy with ambrisentan and tadalafil for the treatment of pulmonary arterial hypertension in children: Real-world experience.

Pediatric pulmonology

Azadeh Issapour, Benjamin Frank, Sarah Crook, Michelle D Hite, Michelle L Dorn, Erika B Rosenzweig, D Dunbar Ivy, Usha S Krishnan

PMID: 34921523 DOI: 10.1002/ppul.25796

Abstract

OBJECTIVE: To describe the safety and tolerability of treatment with ambrisentan and tadalafil in pediatric pulmonary hypertension (PH).

STUDY DESIGN: This retrospective observational two-center study included subjects (≤18 years of age) with PH receiving combination therapy with ambrisentan and tadalafil. Before initiating this therapy, many patients were on other therapies for PH. At baseline, patients either received no therapy or monotherapy with a phosphodiesterase 5 inhibitor (PDE5i) or endothelin receptor antagonist (ERA) (Group A), switched from a different PDE5i and ERA (Group B), or were on prostanoid therapy with or without a PDE5i and/or ERA (Group C and D). Demographics, symptoms, and adverse effects were collected. Pre- and postvalues for exercise capacity, hemodynamics, and biomarkers were compared.

RESULTS: There were 43 subjects (26 F, 17 M) ages 4-17.5 years (median 9.3) with World Symposium of PH group 1, 3, and 5. Significant improvements were seen in change scores at follow-up in the entire sample and Group A for 6-min walk distance: +37.0 (6.5-71.0) [p = 0.022], mean pulmonary artery pressure: -6.0 (-14.0 to -3.5) [p = .002], pulmonary vascular resistance: -1.7 (-6.2 to -1.0) [p = .003], NT-proBNP -32.9 (-148.9 to -6.7) [p = .025]. WHO functional class improved in 39.5% and was unchanged in 53.5%; PH risk scores improved in 16%; were unchanged in 56%; and declined in 14%. Three patients discontinued therapy (two headaches, one peripheral edema). Seven patients were hospitalized for worsening disease (2/7 had a Potts shunt placed, 2/7 had an atrial septostomy). There were no deaths or lung transplantation.

CONCLUSIONS: Combination therapy with ambrisentan and tadalafil was well-tolerated, with an acceptable safety profile in a select group of children. This therapy was associated with improved exercise capacity and hemodynamics in children who were treatment naïve or on monotherapy with a PH medication before the initiation of ambrisentan and tadalafil. Based on these early data, further study of combination therapy in pediatric PH is warranted.

© 2021 Wiley Periodicals LLC.

Keywords: ambrisentan; congenital heart disease; endothelin receptor antagonist; hemodynamics; pediatric cardiology; phosphodiesterase 5 inhibitor; pulmonary hypertension; tadalafil; targeted therapy

References

1. Frank B, Ivy D. Diagnosis, evaluation and treatment of pulmonary arterial hypertension in children. Children. 2018;5(4):44. - PubMed
2. Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J. 2011;37(3):665-677. - PubMed
3. 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):834-844. - PubMed
4. Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J. 2019;53(1):1801916. - PubMed
5. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119. - PubMed
6. Kylhammar D, Kjellström B, Hjalmarsson C, et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur Heart J. 2018;39(47):4175-4181. - PubMed
7. Hughes H, Kahl L. Johns Hopkins Hospital. The Harriet Lane Handbook. 21st ed. Elsevier Inc; 2017. - PubMed
8. Takatsuki S, Rosenzweig EB, Zuckerman W, Brady D, Calderbank M, Ivy DD. Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol. 2013;48(1):27-34. - PubMed
9. Galiè N, Corris PA, Frost A, et al. Treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25):D60-D72. - PubMed
10. Ghofrani HA, Humbert M. The role of combination therapy in managing pulmonary arterial hypertension. Eur Respir Rev. 2014;23(134):469-475. - PubMed
11. van de Veerdonk MC, Huis In T Veld AE, Marcus JT. Upfront combination therapy reduces right ventricular volumes in pulmonary arterial hypertension. Eur Respir J. 2017;49(6):1700007. - PubMed
12. Sitbon O, Sattler C, Bertoletti L, et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J. 2016;47(6):1727-1736. - PubMed
13. Sitbon O, Gaine S. Beyond a single pathway: combination therapy in pulmonary arterial hypertension. Eur Respir Rev. 2016;25(142):408-417. - PubMed
14. Wacker J, Weintraub R, Beghetti M. An update on current and emerging treatments for pulmonary arterial hypertension in childhood and adolescence. Expert Rev Respir Med. 2019;13(2):205-215. - PubMed
15. Ivy DD, Abman SH, Barst RJ, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol. 2013;62:D117-D126. - PubMed
16. Zijlstra WMH, Douwes JM, Rosenzweig EB, et al. Survival differences in pediatric pulmonary arterial hypertension: clues to a better understanding of outcome and optimal treatment strategies. J Am Coll Cardiol. 2014;63:2159-2169. - PubMed
17. Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894-2903. - PubMed
18. Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012;33(5):683-688. - PubMed
19. Sabri MR, Beheshtian E. Comparison of the therapeutic and side effects of tadalafil and sildenafil in children and adolescents with pulmonary arterial hypertension. Pediatr Cardiol. 2014;35(4):699-704. - PubMed
20. von Keitz A, Rajfer J, Segal S, et al. A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil. Eur Urol. 2004;45(4):499-509. - PubMed
21. Galiè 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(23):3010-3019. - PubMed
22. Zuckerman WA, Leaderer D, Rowan CA, Mituniewicz JD, Rosenzweig EB. Ambrisentan for pulmonary arterial hypertension due to congenital heart disease. Am J Cardiol. 2011;107(9):1381-1385. - PubMed
23. Letairis® (ambrisentan) [package insert]. Foster City, CA; Gilead Sciences, Inc.; Revised August, 2019. - PubMed
24. Efficacy and Safety of Ambrisentan in Children 8-18yrs [Clinical Trial]. ClinicalTrials.gov Identifier: NCT01332331. https://clinicaltrials.gov/ct2/show/NCT01332331. - PubMed
25. Spence R, Mandagere A, Harrison B, Dufton C, Boinpally R. No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. J Pharm Sci. 2009;98(12):4962-4974. - PubMed
26. Paul GA, Gibbs JSR, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol. 2005;60(1):107-112. doi:10.1111/j.1365-2125.2005.02383 - PubMed
27. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64(1):43-50. - PubMed
28. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008;48(5):610-618. doi:10.1177/0091270008315315 - PubMed
29. Rosenzweig EB. Tadalafil for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2010;11(1):127-132. doi:10.1517/14656560903413542 - PubMed
30. Ryan JJ, Rich JD, Maron BA. Building the case for novel clinical trials in pulmonary arterial hypertension. Circulation: Cardiovascular Quality and Outcomes. 2015;8(1):114-123. - PubMed
31. Fox BD, Shtraichman O, Langleben D, Shimony A, Kramer MR. Combination therapy for pulmonary arterial hypertension: a systematic review and meta-analysis. Can J Cardiol. 2016;32(12):1520-1530. doi:10.1016/j.cjca.2016.03.004 - PubMed
32. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394-403. - PubMed
33. Oudiz RJ, Brundage BH, Gali N, et al. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol. 2012;60(8):768-774. - PubMed
34. Bennett D, Marcus R, Stokes M. Incidents and complications during pediatric cardiac catheterization. Paediatr Anaesth. 2005;15(12):1083-1088. - PubMed
35. Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting survival in patients with pulmonary arterial hypertension: the REVEAL Risk Score Calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies. Chest. 2019;156(2):323-33. - PubMed

Publication Types

• Journal Article

Grant support

• Jayden de Luca Foundation (Eagle, Idaho)
• UL1 TR002535/TR/NCATS NIH HHS/United States
• UL1 TR002535/TR/NCATS NIH HHS/United States