EPITOME-2

An Open-label Study Assessing the Transition to a New Formulation of Intravenous Epoprostenol in Patients With Pulmonary Arterial Hypertension

Olivier Sitbon, MD; Marion Delcroix, MD; Emmanuel Bergot, MD; Anco B. Boonstra, MD; John Granton, MD; David Langleben, MD; Pilar Escribano Subías, MD; Nazzareno Galiè, MD; Thomas Pfister, PhD; Jean-Christophe Lemarié, MSc; Gérald Simonneau, MD

Disclosures

Am Heart J. 2014;167(2):210-217. 

In This Article

Abstract and Introduction

Abstract

Background Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience.

Methods The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication.

Results Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience.

Conclusions Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience.

Introduction

Intravenous (IV) epoprostenol sodium was first licensed as a pulmonary arterial hypertension (PAH) treatment in 1995 based on improved functional and exercise capacity and survival over conventional therapy in randomized controlled trials.[1,2] To date, IV epoprostenol is the only agent recommended as a first-line treatment for patients with severe PAH categorized as New York Heart Association (NYHA) functional class (FC) IV.[3,4]

Owing to its short half-life in aqueous biological fluids, epoprostenol must be continuously administered through a central venous catheter using a portable pump.[5] Epoprostenol degradation is also rapid in aqueous solutions that are typically used for IV administration. Therefore, epoprostenol sodium is formulated as a lyophilized powder that needs to be reconstituted and diluted before IV infusion. Degradation of epoprostenol in solution is slowed by elevated pH and refrigerated temperatures. Flolan(GlaxoSmithKline, Durham, NC) is an epoprostenol sodium formulation that contains the excipients glycine and mannitol (epoprostenol GM). Freshly prepared solutions of epoprostenol GM must be administered within 8 to 12 hours at room temperature or within 24 hours if maintained at 2°C to 8°C using frozen gel packs.[6,7] As a result, patients on epoprostenol GM therapy need to prepare fresh IV solution and change the medication cassettes every 12 hours, or every 24 hours if using frozen gel packs.[6,7] The inconvenience of epoprostenol therapy could be alleviated to some degree by eliminating the need for frozen gel packs and decreasing the frequency of fresh medication preparation and changing medication cassettes.

Based on a previous formulation,[8] a new formulation of epoprostenol sodium has been developed (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) containing the excipients arginine and sucrose (epoprostenol AS). The new formulation results in an improved stability of epoprostenol in solution. Depending on the concentration, the IV solutions maintain the potency of epoprostenol at room temperature for up to 72 hours, when freshly prepared, or up to 48 hours after refrigerated storage for up to 8 days.[9] A pharmacokinetic comparison of epoprostenol GM and epoprostenol AS demonstrated that the formulations met the criteria for bioequivalence.[10]

The objectives of EPITOME-2 were to assess dose adjustments and the effects on efficacy, safety and tolerability, and quality of life of patients with PAH transitioning from epoprostenol GM to the new formulation, epoprostenol AS.

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