The potential for inhaled treprostinil in the treatment of pulmonary arterial hypertension

Abstract

Inhaled treprostinil is a safe and well-tolerated approved pharmaceutical for the treatment of pulmonary arterial hypertension. In a series of open-label studies and in the pivotal trial with 253 patients, this long-acting prostacyclin analogue demonstrated pronounced pulmonary selectivity of vasodilatory effects, improved physical capacity and excellent tolerability and safety following aerosol administration. For efficient treatment, only four daily inhalations of treprostinil are necessary compared with six to nine in iloprost aerosol therapy. This review describes in detail the development of inhaled treprostinil, starting with intravenous epoprostenol followed by inhaled iloprost and subcutaneous treprostinil, all three representing well-established and widely approved prostanoid therapies for pulmonary hypertension.

In order to circumvent the drawbacks of intravenous epoprostenol, stable prostacyclin analogues with similar pharmacological properties have been investigated. In addition, alternative routes of administration have been proposed and evaluated, mainly inhaled and subcutaneous delivery. The concept of inhaled treprostinil was to combine the pulmonary selectivity of an aerosolized vasodilator with the long-acting effects of a stable prostacyclin analogue.

Pulmonary arterial hypertension remains, however, a severe, life-threatening disease, in spite of the enormous progress in specific drug therapy over the last decade. Therefore, further improvement of drug therapy will be essential, with clear potential for inhaled treprostinil: a reduction of inhalation frequency and duration would markedly improve quality of life and compliance, and a longer-lasting local prostanoid effect might further enhance the efficacy of inhaled treprostinil. The advantageous pharmacological properties of treprostinil offer the opportunity to establish a convenient metered dose inhaler as a delivery system, to combine inhaled treprostinil with available or future drugs for pulmonary arterial hypertension, or to develop sustained release formulations of treprostinil suitable for inhalation based on liposomes or biodegradable nanoparticles.

Pulmonary hypertension

Pulmonary arterial hypertension (PAH) still remains a severe, life-threatening disease in spite of the enormous progress in specific drug therapy over the last decade. The main pathophysiological findings in this devastating disease, increases in pulmonary artery pressure and vascular resistance, result in a markedly reduced exercise capacity and dyspnoea as prominent clinical symptoms. Patient death is most closely associated with elevated right atrial pressure and decreased cardiac output as signs of progressive right heart failure. Until recently, the prognosis of PAH was very poor, with patients having a median life expectancy of only about 2.8 years after diagnosis [D'Alonzo et al. 1991]. The modern specific drug therapy of PAH, including prostacyclins, endothelin receptor antagonists and phophodiesterase-5 inhibitors, has increased the estimated median life expectancy to a maximum of 6 years [McLaughlin et al. 2004]. A significant portion of about 50% of patients surviving the first 2 years under drug therapy show, however, insufficient clinical improvement with recurrent or persisting dyspnoea and fatigue [Provencher et al. 2006]. Even in the modern management era, PAH remains a progressive, fatal disease with mortality most closely associated with male gender, right ventricular haemodynamic function, and limited exercise capacity [Humbert et al. 2010].

Pulmonary hypertension (PH) is classified according to the summary from the fourth world conference on pulmonary hypertension in Dana Point (USA) [Simonneau et al. 2009]. The guidelines published in the European Heart Journal and European Respiratory Journal give an excellent overview on classification, pathobiology and pathophysiology, epidemiology and prognosis as well as on diagnosis and treatment of PH [Galiè et al. 2009a, 2009b]. PAH represents the first group in the clinical classification of PH, occurring idiopathic and heritable or in association with a variety of conditions, such as connective tissue diseases (CTDs), congenital heart diseases, portal hypertension, human immunodeficiency virus infection, intake of appetite-suppressant drugs or toxins. In recent studies incidence and prevalence of PAH was reported to range from 2.4 to 7.6 annual cases per million [Humbert et al. 2006] and 15 to 56 per million [Peacock et al. 2007], respectively.

The prominent pathological characteristics in PAH comprise remodelling and proliferation with intimal fibrosis, medial hypertrophy and adventitial thickening, in situ thrombosis and persistent vasoconstriction of small arteries in the pulmonary circulation [Galiè et al. 2009a]. A lack of endogenous prostacyclin [Christman, 1998] secondary to downregulation of prostacyclin synthase [Tuder et al. 1999] seems to contribute to the development of the vascular pathologies in PAH and represents a solid background for the therapeutic use of prostacyclin and its analogues being potent vasodilators with additional strong antithrombotic [Crutchley and Hirsh, 1991; Czer and Moser, 1983], antiproliferative [Yu et al. 1997; Hara et al. 1995] and anti-inflammatory properties [Boxer et al. 1980].

Intravenous prostacyclin (epoprostenol)

In 1976, prostacyclin with the chemical term prostaglandin I2 (PGI2) was identified to be the ‘endothelium-dependent, aggregation-inhibiting factor with vasodilatory properties’ [Moncada et al. 1976; Whittaker et al. 1976]. In the same year, the chemical analogue epoprostenol was synthesized which was introduced in the 1980s to treat patients suffering from PH. As the molecule is chemically unstable and has a very short biological half-life of only 2–3 minutes, the drug has to be administered continuously by a central venous catheter. First experiences of prostacyclin effects in PH date back to 1980, when prostacyclin was given intravenously in man [O’Grady et al. 1980], and to 1984 with the first report of long-term treatment of idiopathic PAH (formerly named primary PH) with continuous intravenous epoprostenol [Higenbottam et al. 1984]. Later, Higenbottam and colleagues tested the concept of bridging patients with severe idiopathic PAH to lung transplantation by intravenously administered prostacyclin [Higenbottam et al. 1993]; further investigations demonstrated the vasodilatory capacity and clinical benefits of this drug in idiopathic PAH [Barst et al. 1994; Rubin et al. 1990] as well as in forms of secondary PH [Humbert et al. 1999; McLaughlin et al. 1999]. In a randomized, controlled trial in 81 patients with severe idiopathic PAH, intravenous prostacyclin improved exercise capacity as assessed by the 6-min walk distance (6MWD), haemodynamic parameters and survival after a treatment period of 12 weeks compared with conventional therapy alone [Barst et al. 1996]. Together with a second randomized controlled trial in 111 patients with PH due to connective tissue disease (CTD-PAH) [Badesch et al. 2000], also in favour of continuous intravenous prostacyclin, the mentioned pivotal study was the basis for the approval of intravenous epoprostenol for New York Heart Association (NYHA) functional class III and IV patients with idiopathic PAH and CTD-PAH in the United States and many other countries worldwide.

Meanwhile, evidence for persistent clinical benefits of long-term intravenous epoprostenol therapy is available. Two observational cohort analyses in Europe and in the USA demonstrated improved survival of NYHA functional class III and IV patients when compared with the expected survival based on historical data [McLaughlin et al. 2002; Sitbon et al. 2002]. Furthermore, a survey in the USA on the use of epoprostenol showed that a great portion of idiopathic PAH patients waiting for lung transplantation could be withdrawn from the waiting list [Robbins et al. 1998].

Intravenous epoprostenol ranges as gold standard in the therapy of PAH and is recommended, according to the latest published guidelines on PH, as first-line therapy for NYHA functional class IV patients and as additional therapeutic option for patients remaining in NYHA functional class III in spite of oral endothelin receptor antagonist or phophodiesterase-5 inhibitors (alone or in combination) [Galiè et al. 2009a]. However, the chronic intravenous administration of prostacyclin has considerable disadvantages, mainly attributed to the absence of pulmonary and intrapulmonary selectivity of this approach and to the necessity of a permanent central venous access. Systemic side effects (e.g. hypotension, nausea, vomiting, jaw pain, headache, etc.) and ventilation–perfusion mismatch limit the use of intravenous prostacyclin [Ahearn et al. 2002]. The central venous catheter bears the risk of thrombotic, embolic or infectious complications [Higenbottam et al. 1998]; interruption of the infusion may result in serious life-threatening episodes, e.g. increase in symptoms of PH, syncope or death [Cremona and Higenbottam, 1995; Barst et al. 1994]. Moreover, due to frequently observed tachyphylaxis phenomena, a permanent dose escalation to maintain a persistent clinical benefit may have considerable economic consequences [McLaughlin et al. 1998].

In order to circumvent these drawbacks, stable prostacyclin analogues with similar pharmacological properties, namely beraprost, iloprost and treprostinil, have been developed and introduced into therapy of PH. In addition, alternative routes of administration have been proposed and investigated, mainly the inhalative and subcutaneous delivery of the vasoactive agents. Inhaled iloprost and subcutaneous treprostinil are the prominent, well-established and widely approved therapeutic developments which represent the starting point for inhaled treprostinil. Therefore, the major characteristics of these two therapies are described in detail in the following sections.

Inhaled iloprost

Inhalation is a common method to deliver pharmaceuticals directly to the respiratory tract. In fact, the inhalative delivery of broncholytic and anti-inflammatory drugs represent the mainstay in the treatment of chronic obstructive pulmonary disease and asthma; aerosolized antimicrobial agents are regarded as an attractive option for the management of pulmonary infections providing high local drug concentrations while minimizing systemic exposure [Le et al. 2010]. Indeed, inhalation exploits the direct access to the respiratory tract in order to reach a targeted delivery of the drug to the desired site of action thereby improving efficiency and pharmacological effects of therapy and minimizing unwanted systemic adverse reactions. In order to benefit from these advantages the concept of inhaled vasodilators was proposed and developed for the treatment of PH, and reviewed by Gessler et al. 2002. This approach is facilitated by the anatomical properties of the lung where the terminal arterioles, responsible for the greatest portion of vascular resistance, are completely surrounded by alveolar surfaces with only very thin barriers between the alveolar air spaces accessible for the inhaled vasodilator and the artery walls.

First clinical experiences with aerosolized prostacyclin (PGI2) in patients suffering from acute PH due to pneumonia or adult respiratory distress syndrome were reported in the 1990s. After pulmonary deposition of aerosolized PGI2, a selective vasorelaxation in the pulmonary circulation with the maximal vasodilatory effect corresponding to that of intravenous prostacyclin and reduced systemic haemodynamic side effects were observed [Walmrath et al. 1995, 1993]. Furthermore, the intrapulmonary selectivity of the inhalative approach, as a consequence of preferential distribution of aerosolized vasodilators to well-ventilated lung areas, improved the matching of perfusion with ventilation within the lung, thereby reducing right-to-left shunt blood flow and improving oxygenation [Walmrath et al. 1996]. The starting point for inhaled iloprost for treatment of PAH was a clinical observation from Olschewski and colleagues, who demonstrated acute and selective improvement of pulmonary haemodynamics in six PAH patients after iloprost inhalation during right heart catheterization [Olschewski et al. 1996]. In addition, a preserved susceptibility of the pulmonary vasculature, without necessity of dose escalation, was seen after a 1-year period in one patient receiving daily iloprost inhalations. In the following years, a series of studies demonstrated the technical feasibility, potency and pulmonary selectivity as well as safety and good tolerability of aerosolized iloprost in patients with PAH and secondary forms of PH [Olschewski et al. 2003, 1999; Gessler et al. 2001; Hoeper et al. 2000a]. Inhaled iloprost was even suggested as rescue therapy for severely ill PH patients with progressive right heart failure and signs of clinical instability; a situation in which intravenous therapy with vasodilators bears the high risk of arterial hypotension and increasing shunt flow in the lung [Olschewski et al. 1998]. In these patients with extremely poor prognosis inhaled iloprost showed acute preferential pulmonary vasodilation during right-heart catheterization; an improvement of exercise capacity (NHYA functional class and 6MWD) and haemodynamics after a period of 3 months was observed [Olschewski et al. 2000].

In order to evaluate the beneficial effects of inhaled iloprost, selective pulmonary vasodilatation and improvement of haemodynamics and exercise capacity, seen in open-label uncontrolled studies, a randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in 37 European specialist centres [Olschewski et al. 2002]. A total of 203 PH patients in NYHA functional class III or IV were enrolled in this pivotal 12-week trial, comprising 146 PAH patients and 57 patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The primary endpoint of this study consisted of a combination of the following four clinical criteria: (1) improvement in NYHA functional class, (2) increase of at least 10% in the 6MWD, (3) absence of deterioration in the clinical condition and (4) absence of death during the 12 weeks of the study. Iloprost was delivered by a jet nebulizer (HaloLite^TM, Respironics Inc., PA, USA) with a single inhaled dose of 2.5 or 5.0 µg six to nine times daily during waking hours. The primary combined endpoint was reached by 16.8% of patients receiving iloprost compared with 4.9% of patients in the placebo group (p = 0.007). In addition, there was a clear treatment effect on exercise capacity (increase of 36.4 m (p = 0.004) in 6MWD in the iloprost group), NYHA functional class, haemodynamics pre- and postinhalation, as well as on quality of life as evidenced by scores and the Mahler dyspnoea index. Importantly, significantly fewer patients in the iloprost group than in the placebo group prematurely discontinued the study, with death occurring in one (iloprost) versus four (placebo) cases. Overall, the therapy was well tolerated with mild and mostly transient adverse events, mainly related to systemic vasodilation (flushing, headache, jaw pain, hypotension, nausea, syncope etc.). During the treatment period there was no need for dose escalation, the beneficial haemodynamic effects after a single inhaled iloprost dose were comparable at entry and after 12 weeks of therapy. The absence of tachyphylaxis and rebound may be attributed to the intermittent administration of inhaled iloprost with overnight breaks avoiding the desensitization of the prostacyclin receptor usually seen during long-term treatment with continuous intravenous prostacyclin [Hsu and Rubin, 2005].

In conclusion, this trial demonstrated the efficacy and safety of inhaled iloprost for the treatment of severe PAH in NYHA functional class III and IV. As a consequence, inhaled iloprost has been approved in many countries for the therapy of severe PH, e.g. the European Medicines Agency (EMEA) approved inhaled iloprost for treatment of patients with idiopathic PAH (iPAH) in NYHA functional class III, the US Food and Drug Administration (FDA) for the treatment of PAH patients in NYHA functional class III or IV and the Australian Therapeutic Goods Administration (TGA) for the treatment of moderate and severe forms of idiopathic and associated PAH (PAH in NYHA functional class III and IV) as well as inoperable chronic thromboembolic PH.

Meanwhile, data on the long-term effects of inhaled iloprost are available, providing indications for an improvement of exercise capacity and pulmonary haemodynamics after 12 months of iloprost aerosol therapy in 24 patients with iPAH [Hoeper et al. 2000b]. In an observational study over 60 months in 67 iPAH patients with inhaled iloprost as first-line vasodilatory monotherapy, overall survival was 79%, 59% and 49% at 1, 3 and 5 years, respectively, compared with the expected survival, when calculated by the NIH formula, of 68%, 46% and 32% at these time points [Opitz et al. 2005]. Event-free survival, defined as freedom from death, transplantation, switch to intravenous therapy or addition of oral therapy, at 1, 3, and 5 years was only 53%, 20% and 13%, respectively. When interpreting these data, it has to be considered that inhaled daily iloprost dose in this study was only approximately 24 µg which is 20% less than in the pivotal study (median inhaled dose of 30 µg per day) and that several new specific drugs (especially oral bosentan and beraprost) for PH became available during the observational period with the necessity to adapt treatment strategies and start combination therapy. In another prospective, multicentre, open-label 2-year clinical trial, 63 patients with severe PH (among 40 patients with iPAH) were enrolled to receive inhaled iloprost six to nine times daily with an inhaled dose of 4 µg each [Olschewski et al. 2010]. Iloprost aerosol therapy evoked no signs of drug-induced toxicity and had only mild to moderate side effects. The 2-year survival was 87% in the iPAH group while the predicted survival was only 63% suggesting a long-term clinical benefit from continued iloprost aerosol therapy.

Effective iloprost aerosol therapy for severe PH requires no less than six daily inhalations with a maximum of nine inhalations per day during waking hours. The frequent inhalations are necessary because of the short half-life of the pharmacodynamic effects of inhaled iloprost in the pulmonary vasculature of about 25 minutes with haemodynamic parameters returning to baseline values within approximately 1 hour [Olschewski et al. 2003]. The recommended iloprost dose is 2.5 or 5.0 µg per inhalation (as delivered at the mouthpiece of the nebulizer), the used nebulizers generally take 5–10 minutes to deliver these doses. In summary, this results in a cumbersome inhalation procedure with a total duration of up to 90 minutes per day, which is, together with the unavoidable night break, regarded as the major drawback of iloprost aerosol therapy [Gessler et al. 2008].

Subcutaneous treprostinil

Treprostinil (C₂₃H₃₄O₅, MW 390.52) is a synthetic, tricyclic benzindene analogue of prostacyclin which is chemically stable at room temperature and neutral pH in either water, 0.9% sodium chloride or 5% dextrose solution [Phares et al. 2003]. This long-acting prostanoid can be administered subcutaneously and intravenously with bioequivalence at steady state and comparable pharmacokinetics, e. g. elimination half-lives of intravenous versus subcutaneous treprostinil of 4.4 versus 4.6 hours, respectively [Laliberte et al. 2004]. As subcutaneous treprostinil offers several advantages over intravenous epoprostenol, such as easier drug handling, a less cumbersome delivery system, no need for central venous catheter and decreased a risk of rebound after temporary interruption of infusion, this compound and the route of administration were intensively investigated and brought to approval. The large, pivotal 12-week clinical trial with subcutaneous treprostinil was conducted in parallel arms in North America and Europe and enrolled a total of 470 patients with PAH (NYHA functional class II, III and IV) [Simonneau et al. 2002]. The primary endpoint of this multicenter, randomized, double-blind, placebo-controlled study was exercise capacity as defined by the maximum 6MWD. Principal reinforcing endpoints were a composite score of 16 predefined signs or symptoms of PAH, the dyspnoea fatigue rating and the number of deaths, lung transplantation or discontinuation for clinical deterioration. Borg dyspnoea scale assessing shortness of breath immediately after the 6MWD test, haemodynamics measured by right heart catheterization and quality of life using a questionnaire were secondary endpoints. Treprostinil was administered subcutaneously with a microinfusion pump starting with an initial dose of 1.25 ng/kg/min and possible dose escalation to a maximum allowable dose of 22.5 ng/kg/min at week 12. Exercise capacity improved in the treprostinil group and remained virtually unchanged with placebo, the between treatment group difference in median 6MWD was 16 m (p < 0.006). The reinforcing endpoints signs and symptoms of PAH as well as the dyspnoea fatigue rating were significantly improved in favour of treprostinil; total number of deaths, transplantations and discontinuations was 13 patients in the treprostinil group versus 16 patients in the placebo group. In addition, almost all secondary endpoints were significantly improved in patients receiving treprostinil. The relatively moderate difference in the 6MWD in this study may be explained by the inclusion of less-compromised patients (53 patients in NYHA functional class II) and the relatively low doses of treprostinil applied subcutaneously. In fact, the final doses achieved in the treprostinil group were only 9.3 ng/kg/min (19.1 ng/kg/min in the placebo group), far below the maximum target dose in the study of 22.5 ng/kg/min, which is still relatively low compared with current clinical practice. Interestingly, the sickest patients displayed the most important improvements in exercise capacity, and a positive relationship between the dose of treprostinil and the increase in 6MWD could be observed. Adverse events and side effects were in most cases related to the infusion site (pain, reaction and bleeding) and to the use of prostacyclins such as headache, nausea, jaw pain, vasodilation etc. None of the life-threatening complications of intravenous epoprostenol therapy were observed in the study. In conclusion, this study demonstrated that chronic subcutaneous treprostinil is an effective therapy with an acceptable safety profile in patients with PAH. Consequently, subcutaneous treprostinil was approved by the FDA for the treatment of NYHA functional class II–IV PAH in 2002 and by the EMEA for PAH NYHA functional class III. More recently, the FDA also approved intravenous treprostinil on the basis of trials demonstrating bioequivalence to subcutaneous treprostinil [McSwain et al. 2008; Tapson et al. 2006; Laliberte et al. 2004] and reports of successful transitioning from i.v. epoprostenol to i.v. treprostinil [Sitbon et al. 2007; Gomberg-Maitland et al. 2005]

The efficacy of long-term subcutaneous treprostinil was evaluated by Lang and colleagues in 99 PAH and 23 inoperable CTEPH patients over 26.2 ± 17.2 months in an open-label phase of a randomized trial [Lang et al. 2006]. NYHA functional class declined and patients retained their improved exercise capacity (approximately 100 m on average) after 3 years, paralleled by a modest increase in the mean treprostinil dose to 40 ng/kg/min. Importantly, event-free survival (no hospitalization due to clinical worsening, no transition to i.v. epoprostenol, no need for combination therapy or atrial septostomy) was 83.2% and 69% at 1 and 3 years, respectively. Overall survival rates (88.6% at 1 year, 83.2% at 3 years) were similar to those reported for i.v. epoprostenol. A second long-term observation studied 860 PAH patients (with a small subset of 6% CTEPH patients) treated with subcutaneous treprostinil up to 4 years [Barst et al. 2006]. Again, the initial clinical improvement was sustained in the majority of patients. However, 199 patients (23%) discontinued the treatment prematurely due to adverse events, 130 patients (15%) received additional specific PAH therapy (bosentan or sildenafil) and 95 patients (11%) were transitioned to alternative prostanoids. Overall survival of patients remaining on treprostinil monotherapy was 88% and 70% at 1 and 4 years, respectively.

The most frequently occurring side effect of subcutaneous treprostinil is local pain at the infusion site, leading to significant numbers of treatment discontinuation (approximately 6–15%).

Inhaled treprostinil

The concept of inhaled treprostinil was developed in order to combine the pulmonary selectivity of inhaled vasodilators with the long-acting effects of stable prostacyclin analogues. First evidence for this approach was obtained in a sheep model of sustained acute PH induced by continuous infusion of the stable thromboxane analogue U-46619 [Sandifer et al. 2005]. The effects of intravenous versus aerosolized treprostinil on pulmonary and systemic haemodynamics were compared showing a significantly greater reduction in pulmonary vascular resistance and pulmonary arterial pressure after aerosol delivery of identical doses of treprostinil. Inhaled treprostinil, even large doses, had only minimal effects on systemic haemodynamics, whereas intravenous treprostinil dose-dependently increased heart rate and cardiac output and decreased left atrial pressure and systemic blood pressure. Furthermore, the time course of the pulmonary vasodilatory effect of inhaled treprostinil was investigated indicating that the duration of action of treprostinil was about three times that of inhaled epoprostenol.

Almost at the same time, a first clinical observation with inhaled treprostinil in severe PAH was reported [Voswinckel et al. 2006b]. A single dose of 15 µg treprostinil, inhaled in only three breaths, was administered in three patients undergoing right heart catheterization. Inhaled treprostinil caused a significant reduction in pulmonary vascular resistance (mean maximum change from baseline −45.2% ± 17.5%, mean ± SE) for a sustained period of more than 180 min with pronounced pulmonary selectivity. Subsequently, two patients were treated on a compassionate basis with long-term inhaled treprostinil (four daily doses of 15 µg) over 3 months. In both patients NYHA functional class as well as physical capacity improved substantially, and no side effects were observed. This report was the starting point for the evaluation of the potential of inhaled treprostinil in the treatment of PAH with five clinical trials published to date.

In a series of randomized, controlled pilot studies, Voswinckel and colleagues investigated the acute effects of inhaled treprostinil on pulmonary haemodynamics and gas exchange in moderate to severe PAH in a total of 123 patients by means of right heart catheterization [Voswinckel et al. 2006a]. The first study with 44 patients was a randomized, open-label, single-blind crossover study with the objective to compare the acute haemodynamic effects and side effects of inhaled treprostinil with inhaled iloprost in comparable and escalating doses. The drugs were administered consecutively with an observation period of 1 hour after each inhalation. The chronological order of the two inhalations was alternated with half of the patients randomized in a single-blind manner to one of the two groups. The inhaled iloprost dose was 7.5 µg (6-min inhalation time, n = 44), the inhaled treprostinil dose 7.5 µg (6-min inhalation time, n = 14) and 15 µg (6-min inhalation time, n = 14 and 3-min inhalation time, n = 16). Aerosol delivery of both drugs demonstrated comparable pulmonary vasodilatory potency with marked differences in the times course: the maximum vasodilatory effect was reached significantly later (18 ± 2 min versus 8 ± 1 min, mean ± SEM, p < 0.0001) and lasted considerably longer (even beyond the 1-hour observation period, p < 0.0001) after treprostinil inhalation. In contrast to inhaled iloprost, no reduction of systemic arterial pressure and no systemic effects were noted following treprostinil inhalation, in spite of the doubled treprostinil dose or reduced inhalation time.

The second study (31 patients) was a randomized, open-label, single-blind, placebo-controlled study investigating the pharmacokinetics and pharmacodynamics of escalating treprostinil doses over a period of 180 min after inhalation. A secondary objective was to determine the maximally tolerated treprostinil dose. Half of the patients (n = 16) were randomized to an inhaled dose of 30 µg treprostinil or placebo, subsequent patients received 60 µg (n = 6), 90 µg (n = 6) or 120 µg (n = 3). Inhalation time was 6 minutes for all groups. The maximal decrease of pulmonary vascular resistance (approximately 30% from baseline) was comparable for all doses of treprostinil; however, a extended duration of pulmonary vasodilation was noted for the 60 µg, 90 µg and 120 µg doses surpassing the 3-hour observation period. Plasma concentrations of treprostinil peaked 10–15 minutes after inhalation. Importantly, even at the highest doses, treprostinil had only minor effects on systemic arterial pressure, but oxygen saturation decreased significantly at the 120 µg dose. The observed adverse events bad taste, decrease in oxygen saturation and bronchoconstriction were attributed to metacresol in the used treprostinil solution. Indeed, when using metacresol-free treprostinil solution in the third study, these side effects no longer occurred. The primary objective of the third randomized, open-label, single-blind study (48 patients) was to find out the shortest possible inhalation time for a 15 µg treprostinil dose. The drug was applied in 18 (n = 6), 9 (n = 6), 3 (n = 21), 2 (n = 7) or 1 breath(s) (n = 8), and haemodynamics and gas exchange were assessed for 120–180 minutes. All modes were well tolerated with only minor side effects, each mode achieving comparable, sustained pulmonary vasodilation. In conclusion, inhaled treprostinil exerted pronounced pulmonary selectivity and sustained pulmonary vasodilation, high concentrations of treprostinil were well tolerated allowing drug delivery within one single breath.

The concept of metered dose inhaler (MDI) delivery of treprostinil was further validated in a randomized, open label study in 39 patients with PAH [Voswinckel et al. 2009]. A dose of 30, 45 and 60 µg was delivered within seconds by a MDI, inducing significant acute haemodynamic responses in the pulmonary circulation without side effects or clinically relevant affection of systemic vascular resistance and pressure. Moreover, no impact of inhaled treprostinil on ventilation/perfusion matching was found in five patients with pre-existing disturbed gas exchange as assessed by the multiple gas elimination technique.

Acute haemodynamic effects and impact on gas exchange of the combination of oral sildenafil and inhaled treprostinil were investigated in a mixed cohort of PH patients (n = 28 PAH, n = 17 CTEPH, n = 5 lung fibrosis). Doses of 15 µg or 30 µg treprostinil, inhaled 1 hour after 50 mg oral sildenafil, induced an additive, pulmonary selective vasodilatation in PAH and CTEPH patients. The combination was well tolerated without relevant side effects or impairment of gas exchange [Voswinckel et al. 2008].

The safety and efficacy of inhaled treprostinil on top of oral bosentan was investigated in an open-label, multicentre study [Channick et al. 2006]. Twelve patients with symptomatic PAH were divided into two groups (n = 6 each) receiving either a total dose of 30 or 45 µg treprostinil in four daily inhalations of short duration (less than 1 minute). Haemodynamics were assessed by right heart catheterization at baseline and week 12; physical capacity (6MWD), NHYA functional class and adverse events were additionally monitored at week 6. After 12 weeks of treatment, significant improvements of pulmonary haemodynamics were observed with virtually unchanged systemic blood pressure. The acute vasodilatory effect of treprostinil peaked 45 minutes after inhalation and lasted as long as 3 hours. The plasma concentration of treprostinil in the systemic circulation was dose-dependent reaching a maximum after 15 and 45 minutes for the 30 and 45 µg regimen, respectively. The half-life of inhaled treprostinil was less than 1 hour (44–52 minutes), supporting a local, sustained effect on pulmonary vasculature. Importantly, significant improvements in the 6MWD, as well pre- (+49 m) as postinhalation (+67 m), were observed with a trend to better exercise capacity in the 45 µg group. Inhaled treprostinil was safe and well tolerated; transient symptoms such as sore throat, headache and cough had no negative influence on the observed excellent compliance with therapy.

The pivotal trial studied the addition of inhaled treprostinil to oral sildenafil or bosentan in 235 PAH patients with NYHA functional class III (98%) and IV symptoms [McLaughlin et al. 2010]. In this 12-week, randomized, placebo-controlled, double-blind multicentre study patients, already treated with either bosentan (70%) or sildenafil for at least 3 months before study entry, were randomized to inhaled treprostinil (maximum single dose of 54 µg in nine breaths) or placebo four times daily. The primary endpoint was peak 6MWD (within 10–60 minutes after inhalation) at 12 weeks, secondary endpoints included time to clinical worsening, defined as death, transplantation, hospital stay or initiation of additional approved specific PAH therapy, Borg dyspnoea score, NYHA functional class, trough 6MWD (at least 4 hours after inhalation), quality of life and predefined PAH signs or symptoms. In addition, the biomarker N-terminal-pro brain natriuretic peptide (NT-proBNP) was measured. The mean dose of study drug was 50 ± 10 µg in the inhaled treprostinil group and 52 ± 7 µg in the inhaled placebo group; 23 patients withdrew from the study prematurely (13 in the treprostinil group, 10 in the placebo group). The Hodges–Lehmann between-treatment median difference in change from baseline in peak 6MWD was 20 m at week 12 (p = 0.0004) with greater improvements in patients receiving bosentan therapy compared with sildenafil therapy. In addition, the change in 6MWD improved as early as week 6 (19 m, p = 0.0001) and was also present at trough 6MWD at week 12 (14 m, p = 0.006). Quality of life measures and NT-proBNP displayed significant improvements with reduction in NT-proBNP plasma levels in patients treated with inhaled treprostinil reflecting a beneficial effect on right ventricular function. This is meaningful as plasma NT-proBNP concentrations correlate with severity and prognosis in PAH [Fijalkowska et al. 2006; Leuchte et al. 2004; Nagaya et al. 2000]. In all other endpoints there were no significant improvements. Inhaled treprostinil was safe and well tolerated; cough was the most common adverse event and typical side effects of prostanoid therapy were reported.

The FDA has approved inhaled treprostinil for the treatment of PAH in patients with NYHA functional class III symptoms associated with WHO Group I PAH.

Future potential improvements of inhaled treprostinil

For the application of treprostinil a relatively bulky and unhandy ultrasonic nebulizer with many necessary accessories is to be used. One ampoule of the medication has to be filled in the medicine cup of the nebulizer daily, and the chamber of the device must be filled with distilled water. The handling of the device is rather complicated requiring multiple steps for assembly and daily cleaning procedures. Furthermore, in spite of the longer-lasting haemodynamic effects of this stable prostacyclin analogue, four daily inhalations with a duration of 2–3 minutes each are necessary.

A reduction of inhalation frequency and duration would markedly improve quality of life and compliance of patients; and a longer-lasting local prostanoid effect might further improve the benefits of inhaled treprostinil therapy.

The possibility to deliver treprostinil effectively and safely in high concentrations within seconds offers the option to introduce a convenient, portable multidose soft mist inhaler or MDI into treprostinil aerosol therapy. Such a delivery system surely will improve the quality of life and compliance of patients.

Over the past years, the body of acquired knowledge and expertise in the treatment of PH has clearly indicated that monotherapy alone is in many cases not sufficient to keep patients clinically stable over many years, especially when suffering from severe forms of this disease. Therefore, the combination of different specific drugs was proposed and object of several trials, as for example in the pivotal study for inhaled treprostinil. Owing to the proven efficacy as well as to the advantages in the route of administration and in the pharmacology of this stable prostacyclin analogue, inhaled treprostinil may represent the preferred candidate in the group of prostanoids. However, further trials with one or more drugs selected from the established class of endothelin receptor antagonists or phophodiesterase-5 inhibitors as well as from emerging new classes, such as stimulators or activators of soluble guanylate cyclase, tyrosine kinase inhibitors and rho kinase inhibitors, are necessary to demonstrate beneficial synergistic effects and to work out possible adverse drug interactions.

An intriguing novel strategy for further improvements of inhaled treprostinil is the development of treprostinil-containing controlled release formulations such as liposomes or nanoparticles designed for aerosol delivery. Such formulations will not only help to reduce the frequency of daily inhalations but also to facilitate sustained release of the vasoactive drug locally in the diseased lung without treatment gap during night time. Recently, iloprost-loaded liposomes have been synthesized displaying efficient iloprost encapsulation and high stability during aerosolization by a piezoelectrical nebulizer [Kleemann et al. 2007]. Nanotechnology offers new possibilities for the design of drug carriers and for targeted therapy, e.g. drug-containing nanostructured polymer particles facilitating controlled drug release by diffusion or permeation processes or by degradation of the polymer matrix. Biocompatible degradable nanoparticles intended for inhalation were already synthesized, characterized and evaluated as drug carriers for pulmonary sustained release [Beck-Broichsitter et al. 2010, 2009; Packhaeuser et al. 2009; Dailey et al. 2006, 2003a, 2003b].

Conclusion

Inhaled treprostinil is a safe and well-tolerated approved pharmaceutical for the treatment of PAH combining the pulmonary selectivity of an aerosolized vasodilator with the long-acting effects of a stable prostacyclin analogue. For efficient therapy improving physical capacity of patients, four daily inhalations of treprostinil are necessary. The advantageous pharmacological properties of this compound offer the opportunity to establish a convenient MDI as a delivery system, to combine inhaled treprostinil with available or future specific drugs for PAH, or to develop sustained release formulations of treprostinil suitable for inhalation on the basis of liposomes or biodegradable nanoparticles.