Favorable Effects of Inhaled Treprostinil in Severe Pulmonary Hypertension
Results From Randomized Controlled Pilot Studies
Robert Voswinckel, MD*,
Beate Enke, MD*,
Frank Reichenberger, MD*,
Markus Kohstall, MD*,
Andree Kreckel, MD*,
Stefanie Krick, MD*,
Henning Gall, MD*,
Tobias Gessler, MD, PhD*,1,
Thomas Schmehl, PhD*,1,
Hossein A. Ghofrani, MD*,2,
Ralph Theo Schermuly, PhD*,
Friedrich Grimminger, MD, PhD*,3,
Lewis J. Rubin, MD ,4,
Werner Seeger, MD*,5 and
Horst Olschewski, MD*, ,6,*
* Department of Internal Medicine, University Hospital Giessen, Giessen, Germany
Division of Pulmonary and Critical Care Medicine, University of California, San Diego School of Medicine, La Jolla, California
Division of Pulmonology, Medical University Graz, Graz, Austria.
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Figure 1 Response of pulmonary vascular resistance (PVR) to inhaled treprostinil versus iloprost: period effects. (A) First inhalation session with treprostinil (n = 22) versus first inhalation session with iloprost (n = 22). (B) Second inhalation session with treprostinil (n = 22) versus second inhalation session with iloprost (n = 22). The PVR decrease with treprostinil was delayed and prolonged compared with that for iloprost. Because of carryover effects from the first period, in the second period, the effects of both drugs appeared shortened. Data are shown as percent of baseline values (mean ± 95% confidence interval).
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Figure 2 Response of pulmonary vascular resistance (PVR) and systemic arterial pressure (SAP) to inhalation of treprostinil versus iloprost: dose effects. (A) Inhalation of 7.5 µg iloprost (in 6 min) versus 7.5 µg treprostinil (6 min) (n = 14, in randomized order). (B) Inhalation of 7.5 µg iloprost (6 min) versus 15 µg treprostinil (6 min) (n = 14, in randomized order). (C) Inhalation of 7.5 µg iloprost (6 min) versus 15 µg treprostinil (3 min) (n = 16, in randomized order). Data are shown as percent of baseline values (mean ± 95% confidence interval). Circles = iloprost; triangles = treprostinil.
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Figure 3 Hemodynamic response to inhalation of treprostinil versus iloprost. Data from 44 patients who inhaled both drugs in randomized order, shown as percent of baseline values (mean ± 95% confidence interval). Abbreviations as in Table 1.
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Figure 4 Pharmacodynamics after treprostinil inhalation versus placebo. Placebo or treprostinil in doses of 30, 60, or 90 µg were inhaled (mean ± 95% confidence interval). Maximal decrease of pulmonary vascular resistance (PVR) was comparable for all doses. The duration of pulmonary vasodilation (PVR decrease) seemed to be dose dependent. Abbreviations as in Table 1.
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Figure 5 Areas between the placebo and the treprostinil curves (ABC). The ABC was calculated for a 3-h period after application of inhaled treprostinil or placebo from the relative changes of hemodynamic parameters (mean ± 95% confidence interval). Abbreviations as in Table 1.
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Figure 6 Hemodynamic responses to the application of 15 µg inhaled treprostinil. The inhalation time was minimized by increasing treprostinil concentration. A pulse of aerosol was generated every 6 s. Treprostinil aerosol was inhaled in concentrations of 100 µg/ml (18 pulses; n = 6), 200 µg/ml (9 pulses; n = 6), 600 µg/ml (3 pulses; n = 21), 1,000 µg/ml (2 pulses; n = 7), and 2,000 µg/ml (1 pulse; n = 8). Placebo data correspond to Figure 4. Data are shown as mean ± 95% confidence interval. Abbreviations as in Table 1.
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Figure 7 Areas between the placebo curve and the responses to 15 µg treprostinil applied at increasing concentrations to minimize inhalation time. For details of aerosol generation, see Figure 5. Mean ± SEM of relative changes of hemodynamic parameters (observation time, 120 min). Abbreviations as in Table 1.
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Figure 8 Pharmacokinetics of treprostinil after one application of inhaled treprostinil (TRE). Treprostinil plasma levels after application of 30, 60, 90, or 120 µg TRE (6 min inhalation period; experiments correspond to those shown in Figs. 4 and 5). Data with error bars represent mean ± SEM.
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