Abstract
Treatments of pulmonary hypertension (PH) continue to evolve with approval of new
therapies. The currently FDA approved inhaled PH therapies include inhaled iloprost
for group 1 pulmonary arterial hypertension (PAH), inhaled treprostinil solution and
treprostinil dry powder inhaler for both group 1 PAH and group 3 PH associated with
interstitial lung disease (PH-ILD). Inhaled treprostinil was recently approved for
group 3 PH-ILD based on the results of INCREASE trial and the newer formulation of
treprostinil dry powder that comes with a new inhaler was recently approved for both
group 1 PAH and group 3 PH-ILD based on BREEZE study. The pipeline for inhaled PH
therapies includes several promising molecules that can enrich the current PH therapeutic
era and mitigate several systemic side effects by directly delivering the drug to
the target organ. In this review article we summarize the evidence for the currently
approved inhaled PAH/PH therapies, discuss the available inhalation devices, present
a roadmap for successful treatment strategy, and present several inhaled PAH/PH therapies
in the pipeline.
Key Indexing Terms
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References
- Mortality in pulmonary arterial hypertension in the modern era: early insights from the pulmonary hypertension association registry.J Am Heart Assoc. 2022; 11e024969
- 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Respir J. 2022;
- Prostacyclin therapies for the treatment of pulmonary arterial hypertension.Eur Respir J. 2008; 31: 891-901
- Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension.Chest. 2003; 124: 1294-1304
- Inhaled iloprost for severe pulmonary hypertension.N Engl J Med. 2002; 347: 322-329
- Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension.Eur Respir J. 2006; 28: 691-694
- Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.Am J Respir Crit Care Med. 2006; 174: 1257-1263
- Long-term therapy with inhaled iloprost in patients with pulmonary hypertension.Respir Med. 2010; 104: 731-740
- Efficacy and safety of inhaled iloprost in japanese patients with pulmonary arterial hypertension - insights from the IBUKI and AIR studies.Circ J. 2016; 80: 835-842
- Inhaled iloprost induces long-term beneficial hemodynamic changes in patients with pulmonary arterial hypertension receiving combination therapy.Pulm Circ. 2022; 12: e12074
- Inhaled Iloprost improves right ventricular load-independent contractility in pulmonary hypertension.Am J Respir Crit Care Med. 2022; 206: 111-114
- Inhaled treprostinil: a therapeutic review.Drug Des Devel Ther. 2012; 6: 19-28
- Potent effects of aerosol compared with intravenous treprostinil on the pulmonary circulation.J Appl Physiol. 1985; 99 (2005): 2363-2368
- Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial.J Am Coll Cardiol. 2010; 55: 1915-1922
- Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the treprostinil sodium inhalation used in the management of pulmonary arterial hypertension (TRIUMPH) study open-label extension.J Heart Lung Transplant. 2011; 30: 1327-1333
- Impact of inhaled treprostinil on risk stratification with noninvasive parameters: a post hoc analysis of the TRIUMPH and BEAT studies.Pulm Circ. 2020; 102045894020977025
- Survival and drug persistence in patients receiving inhaled treprostinil at doses greater than 54 µg (nine breaths) four times daily.Pulm Circ. 2021; 1120458940211052228
- Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease.N Engl J Med. 2021; 384: 325-334
- The importance of early treatment with inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease: a post-hoc analysis of the INCREASE open-label extension.in: Proceedings of the annual world congress of the pulmonary vascular research institute. 2022: A021 (n/a. Pulmonary Circulation)
- Inhaled treprostinil dosage in pulmonary hypertension associated with interstitial lung disease and its effects on clinical outcomes.Chest. 2022;
- Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.Lancet Respir Med. 2021; 9: 573-584
- Efficacy of inhaled treprostinil on multiple disease progression events in patients with pulmonary hypertension due to parenchymal lung disease in the INCREASE trial.Am J Respir Crit Care Med. 2022; 205: 198-207
- Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study.Lancet Respir Med. 2021; 9: 1266-1274
- Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis.BMJ Open Respir Res. 2022; 9
- The antifibrotic effects of inhaled treprostinil: an emerging option for ILD.Adv Ther. 2022; 39: 3881-3895
- BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension.Pulm Circ. 2022; 12: e12063
- Dry powder inhalers: upcoming platform technologies for formulation development.Ther Deliv. 2019; 10: 551-554
Koninklijke Philips N.V. I-neb AAD System - Battery Powered Drug Delivery System, https://www.usa.philips.com/healthcare/product/HC85167/i-neb-battery-powered-drug-delivery-system.
- Intelligent nebulizers in the age of the internet: the I-neb adaptive aerosol delivery (AAD) system.J Aerosol Med Pulm Drug Deliv. 2010; 23 (Suppl 1): iii-iiv
Corporation UT. Tyvaso Inahaltion System TD-300: Instrucions for Use. 2021.
Corporation UT. Tyvaso Inhalation System TD-100: Instructions for Use. 2014.
Corporation UT. Tyvaso Inhalation Powder DPI: Instructions for Use. 2022.
- Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study.Am J Respir Crit Care Med. 2011; 183: 1723-1729
- Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension.Hypertens Res. 2006; 29: 123-128
- Superior vasodilation of human pulmonary vessels by vardenafil compared with tadalafil and sildenafil: additive effects of bosentan.Interact Cardiovasc Thorac Surg. 2017; 25: 254-259
- Acute hemodynamic improvement in chronic pulmonary arterial hypertension on dual therapy following RT234 inhalation.Chest. 2020; 158: A2162-A2A63
- A Phase 1 Single and Multiple Ascending Dose (SAD/MAD) Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AV-101, a Novel Inhaled Dry Powder Formulation of Imatinib in Healthy Subjects.American Thoracic Society, San Francisco, CA, USA2022: A3594 (-A94)
- Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study.Circulation. 2013; 127: 1128-1138
- Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.N Engl J Med. 2013; 369: 319-329
- Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC.Respir Res. 2022; 23: 272
- Inhaled nitric oxide therapy in acute bronchiolitis: a multicenter randomized clinical trial.Sci Rep. 2020; 10: 9605
- Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults.Cochrane Database Syst Rev. 2016; CD002787
- Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: a multicenter cohort study.Crit Care. 2022; 26: 304
- A randomized, double-blind, placebo-controlled study of pulsed, inhaled nitric oxide in subjects at risk of pulmonary hypertension associated with pulmonary fibrosis.Chest. 2020; 158: 637-645
- Risk assessment in pulmonary arterial hypertension (PAH): insights from the INSPIRE study with LIQ861.in: Proceedings of the ISHTL 42nd annual meeting & scientific sessions, Boston, MA, USA2022
- Development and characterization of treprostinil palmitil inhalation aerosol for the investigational treatment of pulmonary arterial hypertension.Int J Mol Sci. 2021; 22
- Inhaled liposomal treprostinil (L606) shows extended release in healthy volunteer, as well as prolongs pharmacological effect in hypoxia-induced rat.in: Proceedings of the ERS international congress. 56. European Respiratory Journal, 2020 (1480)
- Platelet-derived growth factor receptor type alpha activation drives pulmonary vascular remodeling via progenitor cell proliferation and induces pulmonary hypertension.J Am Heart Assoc. 2022; 11e023021
- Reversal of experimental pulmonary hypertension by PDGF inhibition.J Clin Invest. 2005; 115: 2811-2821
- Long-term safety and efficacy of imatinib in pulmonary arterial hypertension.J Heart Lung Transpl. 2015; 34: 1366-1375
- Inhaled imatinib for pulmonary arterial hypertension clinical trial: design of the impact phase 2b/3 study design.Chest. 2022; 162 (Nashville, TN, USA): A2325-A2A29
- Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension.Eur Respir J. 2022;
- TORREY, a Phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension.Pulm Circ. 2021; 1120458940211057071
- Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.Lancet Respir Med. 2022; 10: 937-948
Article info
Publication history
Published online: March 13, 2023
Accepted:
March 6,
2023
Received:
December 7,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
