Clinical Research
Pulmonary Vascular Disease
Favorable Effects of Inhaled Treprostinil in Severe Pulmonary Hypertension: Results From Randomized Controlled Pilot Studies

https://doi.org/10.1016/j.jacc.2006.06.062Get rights and content
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Objectives

This study sought to investigate the effects of inhaled treprostinil on pulmonary hemodynamics and gas exchange in severe pulmonary hypertension.

Background

Inhaled iloprost therapy has a proven clinical efficacy in pulmonary arterial hypertension, but this therapy necessitates 6 to 9 inhalation sessions per day. Treprostinil has a longer plasma half-life and might provide favorable properties when applied by inhalation.

Methods

Three different studies were conducted on a total of 123 patients by means of right heart catheterization: 1) a randomized crossover-design study (44 patients), 2) a dose escalation study (31 patients), and 3) a study of reduction of inhalation time while keeping the dose fixed (48 patients). The primary end point was the change in pulmonary vascular resistance (PVR).

Results

The mean pulmonary arterial pressure of the enrolled patients was approximately 50 mm Hg in all studies. In study 1, both treprostinil and iloprost at an inhaled dose of 7.5 μg displayed a comparable PVR decrease, with a significantly different time course (p < 0.001), treprostinil showing a more sustained effect on PVR (p < 0.0001) and fewer systemic side effects. In study 2, effects of inhalation were observed for 3 h. A near-maximal acute PVR decrease was observed at 30 μg treprostinil. In study 3, treprostinil was inhaled at increasing concentrations with a pulsed ultrasonic nebulizer, mimicking a metered dose inhaler. A dose of 15 μg treprostinil was inhaled with 18, 9, 3, 2 pulses, or 1 pulse, each mode achieving comparable, sustained pulmonary vasodilation without significant side effects.

Conclusions

Inhaled treprostinil exerts sustained pulmonary vasodilation with excellent tolerability at relatively low doses and may be inhaled in a few breaths.

Abbreviations and Acronyms

PVR
pulmonary vascular resistance
AUC
area under the curve
ABC
areas between curves
PAP
pulmonary arterial pressure
SAP
systemic arterial pressure

Cited by (0)

This work was financially supported by Lung RX Inc., Satellite Beach, Florida. Dr. Bruce H. Brundage acted as the guest editor for this paper.

1

Drs. Gessler and Schmehl are holders of a patent of the technology of the IloNeb ultrasonic nebulization device.

2

Dr. Ghofrani received grant and contract support from Pfizer Ltd., Altana Pharma AG, Schering AG, and served on the advisory board of Pfizer Ltd.

3

Dr. Grimminger received grant and contract support from Pfizer Ltd. and Altana Pharma AG.

4

Dr. Rubin received research grants from the NIH and industry-sponsored grants; served as a consultant for Actelion, United Therapeutics, Pfizer, Myogen, Schering, Nitrox, MondoBiotech, and CoTherix; and received stock options in United Therapeutics for service on the Scientific Advisory Board.

5

Dr. Seeger received grant and contract support from Schering, Altana Pharma, Myogen Inc. Westminster, LungRX, and Aventis Pharma.

6

Dr. Olschewski was a consultant and investigator for ScheringAG, LungRX, CoTherix, Encysive, and Myogen; received research grants from ScheringAG and LungRX; received treprostinil from Lung RX and inhalation devices from nebu-tec; and used iloprost, sildenafil, and treprostinil off-label for treatment of pulmonary hypertension.