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Clinical Use of Extended-Release Oral Treprostinil in the Treatment of Pulmonary Arterial Hypertension

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Clinical Use of Extended-Release Oral Treprostinil in the Treatment of Pulmonary Arterial Hypertension Integrated Blood Pressure Control Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Clinical use of extended-release oral treprostinil in the treatment of pulmonary arterial hypertension Steven C Pugliese1 Abstract: The development of parenteral prostacyclin therapy marked a dramatic breakthrough Todd M Bull1,2 in the treatment of pulmonary arterial hypertension (PAH). Intravenous (IV) epoprostenol was the first PAH specific therapy and to date, remains the only treatment to demonstrate a mortal- 1Division of Pulmonary Sciences and Critical Care Medicine, Department ity benefit. Because of the inherent complexities and risks of treating patients with continuous of Medicine, 2UCD Pulmonary infusion IV therapy, there is great interest in the development of an oral prostacyclin analog Vascular Disease Center, Division of Pulmonary Sciences and Critical Care that could mimic the benefits of IV therapy. Herein, we highlight the development of oral Medicine and Cardiology, Department prostacyclin therapy, focusing on oral treprostinil, the only US Food and Drug Administration of Medicine, University of Colorado approved oral prostacyclin. Recent Phase III clinical trials have shown the drug to improve Anschutz Medical Campus, Aurora, CO, USA exercise tolerance in treatment-naïve PAH patients, but not patients on background oral therapy. For personal use only. Oral treprostinil appears to be most efficacious at higher doses, but its side effect profile and complexities with dosing complicate its use. While oral treprostinil’s current therapeutic role in PAH remains unclear, ongoing studies of this class of medication should help clarify their role in the treatment of PAH. Keywords: oral treprostinil, pulmonary arterial hypertension, selexipag Introduction: management issues in pulmonary arterial hypertension The first reported case of pulmonary arterial hypertension (PAH), published in 1891 by Romberg,1 described a patient who died suddenly, identifying both right ventricular and pulmonary artery sclerosis without apparent cause. It was not until 1951, fol- Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 54.70.40.11 on 22-Mar-2018 lowing the development of cardiac catheterization, that Dresdale et al2 was able to describe the hemodynamic findings of PAH and coined the term “primary pulmonary hypertension”.2 Nearly 100 years later, the first specific treatment for PAH was the US Food and Drug Administration (FDA)-approved epoprostenol. Barst et al3 published their pivotal findings demonstrating that intravenous (IV) epoprostenol improved 6-minute walk distance (6MWD) and hemodynamics. Though the patient numbers were small and the study duration was short, this remains the only clinical trial in PAH Correspondence: Todd M Bull to demonstrate a mortality benefit to date. Great progress has since been made with UCD Pulmonary Vascular Disease the development and approval of three separate classes of drugs for the treatment of Center, Division of Pulmonary Sciences and Critical Care Medicine and PAH: prostacyclins, endothelin receptor antagonists (ERAs), and phosphodiesterase-5 Cardiology, Department of Medicine, (PDE-5) inhibitors/soluble guanylate cyclase stimulators. To date however, there University of Colorado Anschutz Medical is general agreement that by far the most effective therapy for patients with severe Campus, Research Complex 2, 12700 East 19th Avenue, Aurora, PAH is the parenteral or subcutaneously infused prostanoids. This class of medica- CO 80045, USA tions is also however the most difficult to use. They require placement of a long-term Tel +1 303 724 6044 Email [email protected] tunneled vascular or subcutaneously positioned catheter, extensive patient training, submit your manuscript | www.dovepress.com Integrated Blood Pressure Control 2016:9 1–7 1 Dovepress © 2016 Pugliese and Bull. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/IBPC.S68230 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Pugliese and Bull Dovepress and significant lifestyle modification to accommodate the can occur via cyclic adenosine monophosphate-dependent preparation and administration of a continuously infused mechanisms (ie, inhibition of platelet-derived growth factor, medication. Over the past two decades, considerable effort mitogenic responses) as well as through cyclic adenosine has been directed to the development of an effective and monophosphate-independent mechanisms such as activation tolerable oral prostacyclin with the aim of both increasing of the mitogen-activated protein kinases pathway.10 Prosta- the availability of this class of medication and perhaps ulti- cyclin and its analogs are also able to signal through nuclear mately eliminating the need for IV or subcutaneous (SubQ) receptors such as peroxisome proliferator-activated recep- prostanoid therapy. This review will highlight the develop- tors (PPARs) with differences in their affinity for the three ment of oral prostacyclin therapies focusing specifically on isoforms: PPARα, PPARβ, and PPARγ.10 While the PPARs the use and role of oral treprostinil. have diverse cellular functions, with regard to prostacyclin activation, they appear to be important in vasorelaxation, Overview of prostacyclin vascular endothelial growth factor production, pulmonary pharmacology artery endothelial survival, and inhibition of smooth muscle 10,11,18–20 Prostacyclin, or prostaglandin I2, was first described in 1976 cell proliferation. Because none of these medications by Moncada et al4 who isolated an enzyme from pig and rat have been directly compared in clinical trials, the clinical aortas that inhibited platelet aggregation and caused arterial implications of these differences remain unknown. vasodilation. It is now known that prostacyclin is derived from the vascular endothelium and has potent pulmonary vasodila- The development of oral tory, antiplatelet, and antiproliferative properties.5,6 Patients prostanoid therapy with PAH have decreased prostacyclin production including a Enthusiasm for developing effective alternate routes of deficiency in prostacyclin synthase as well as increases in the administration for prostacyclin therapy fueled a series of vasoconstrictive and prothrombotic prostaglandin thrombox- clinical studies published in 2002 involving SubQ, inhaled, ane.7,8 Prostacyclin exerts its effects primary through the IP and oral prostanoid formulations. Simonneau et al,21 in a For personal use only. receptor, a G-protein-coupled receptor that initially activates Phase III randomized controlled trial (RCT), demonstrated adenylate cyclase with subsequent downstream activation of that SubQ treprostinil improved exercise tolerance (median protein kinase A mediating a host of effects including inhibi- placebo-corrected 6MWD 16 m), dyspnea indices, and hemo- tion of platelet aggregation, relaxation of smooth muscle, and dynamics in PAH patients at 12 weeks compared to placebo. vasodilation of the pulmonary arteries.9 Prostacyclins also However, the medication required continuous infusion, exert anti-inflammatory and antiproliferative effects on a vari- treatment effect was modest compared to IV epoprostenol, ety of cell types.10–13 Epoprostenol is a synthetic prostacyclin and infusion-related site pain led to discontinuation of drug with a half-life (T1/2) of 2–3 minutes and is stable at room in a significant number of patients (8%). During the same temperature for only 8 hours.14 Due to its inherent instability, year, Olschewski et al22 demonstrated (Phase III RCT) that significant effort has been directed toward the development inhaled iloprost led to an improvement in the combined end Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 54.70.40.11 on 22-Mar-2018 of other, more stable prostacyclin analogs including iloprost point of exercise capacity, New York Heart Association (T1/2=20–30 minutes), beraprost (T1/2=40–60 minutes), and (NYHA) functional class (FC), and clinical deterioration in 10,15,16 treprostinil (T1/2=180–270 minutes). While all of the NYHA FC III/IV PAH/inoperable chronic thromboembolic synthetic prostanoids primarily signal through the IP recep- pulmonary hypertension (PH) patients at 12 weeks. However, tor, there are differences in both their selectivity and affinity inhaled iloprost required administration every 2–4 hours and to other prostaglandin receptors that may give them unique patients were often plagued by significant cough, further pharmacologic properties.10 For example, epoprostenol has raising interest for an oral prostanoid formulation. some affinity for the vasoconstrictive prostaglandin 1E (EP1), Beraprost sodium was the first chemically stable and 23 prostaglandin E3 (EP3), and thromboxane (TP) receptors, orally active prostacyclin analog. The initial, large Phase III while treprostinil can also bind the vasodilatory prosta- trial involving oral beraprost (Arterial Pulmonary Hyper- 10,17
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