Inhaled treprostinil: a therapeutic review

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease which, if untreated, leads to right ventricular failure and often death. Several effective therapies are now available for PAH, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. The prostacyclin analog treprostinil has proven efficacious when delivered by subcutaneous or intravenous infusion, and most recently by inhalation. Inhaled treprostinil has been shown to be 64%-72% bioavailable in healthy volunteers. Pilot clinical studies have elucidated the acute hemodynamic effects and relative pulmonary selectivity of this agent, as well as established target dosing in PAH and nonoperable chronic thromboembolic PAH. Likewise, chronically administered inhaled treprostinil resulted in clinical and hemodynamic improvement. Both pilot studies confirmed a satisfactory safety profile in patients with PAH. The pivotal Phase III trial, TRIUMPH-I, demonstrated the efficacy and safety of inhaled treprostinil (target dose of 54 μg four times daily) in PAH patients added to background therapies of bosentan or sildenafil, as assessed by improvements in the primary endpoint, peak six-minute walk distance (median placebo-corrected treatment effect of 20 m), as well as select secondary endpoints. Inhaled treprostinil is approved by the US Food and Drug Administration for patients with World Health Organization Group I PAH to improve exercise ability. Studies establishing effectiveness included predominately patients with New York Heart Association functional class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

Keywords: inhaled; nebulizer; prostacyclin; pulmonary arterial hypertension; treprostinil.

Figure 1

Structural formula of treprostinil. Treprostinil is (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1Hbenz[f]inden-5-yl]oxy]acetic acid. Treprostinil has a molecular weight of 390.52 and a molecular formula of C₂₃H₃₄O₅.

Figure 2

Plasma concentrations following inhalation of various doses of treprostinil.

Figure 3

Tyvaso Inhalation System. Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of the Opti-Neb-ir Model ON-100/7 (NebuTec, Elsenfeld, Germany), an ultrasonic, pulsed-delivery device.

Figure 4

Comparison of acute hemodynamic effects of inhaled treprostinil and inhaled iloprost in patients with pulmonary arterial hypertension. Abbreviations: CO, cardiac output; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; SAP, systemic artery pressure.

Figure 5

Change in six-minute walk distance (6MWD) with inhaled treprostinil in TRIUMPH-1. Primary end-point, change in peak 6MWD for patient receiving background sildenafil (white bars), background bosentan (black bars), and the entire population (solid bars). There was a placebo-corrected improvement of 20 m at 12 weeks in the total population. Results presented as Hodges–Lehman between-treatment median difference.

Figure 6

Distribution of six-minute walk distance (6MWD) improvements from inhaled treprostinil vs placebo groups in TRIUMPH-I. The graph illustrates the percentage of patients who achieved specific improvements in 6MWD at 12 weeks. For example, 31% of patients taking inhaled treprostinil and 12% of patients taking inhaled placebo had an improvement in 6MWD of >50 m at 12 weeks.