A study to compare the effects of different formulations of epoprostenol for injection.

In addition to epoprostenol sodium formulated with glycine-mannitol (epoprostenol GM; Flolan (Registered Trademark); GlaxoSmithKline, North Carolina, USA), 2 other formulations of epoprostenol sodium for injection were recently approved by US FDA for treatment of PAH. All 3 formulations contain the same active ingredient (epoprostenol sodium) but differ with regard to excipients. These modifications confer to the 2 new formulations of epoprostenol sodium, one formulated with arginine-mannitol (epoprostenol AM; Veletri (Registered Trademark) first generation, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland 8) and one formulated with arginine-sucrose (epoprostenol AS, Veletri (Registered Trademark) second generation, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland), an improved stability after reconstitution and dilution when compared to epoprostenol GM. Epoprostenol AM and epoprostenol AS were infused via an intravenous (i.v.) catheter (on the dominant arm) using an ambulatory infusion pump (CADD-Legacy (Registered Trademark) 1, ambulatory infusion pump Model 6400 for continuous delivery) at room temperature. Epoprostenol GM was administered with the pump contained in a special pouch using frozen gel packs to maintain its stability. In each study part, the pharmacokinetics, pharmacodynamics, safety, and tolerability of two different formulations of epoprostenol sodium for injection were assessed, epoprostenol AM and epoprostenol AS in part 1 and epoprostenol AS and epoprostenol GM in part 2. A total of 40 healthy male subjects were enrolled, i.e., 20 in part 1 and 20 different subjects in part 2. Each subject, enrolled either in Part 1 or Part 2, attended two periods separated by a 7-day washout period. Over the two treatment periods of Part 1, treatments with epoprostenol AM and epoprostenol AS were administered in the sequence epoprostenol AM/epoprostenol AS or epoprostenol AS/epoprostenol AM, with 10 subjects per sequence as determined by randomization. Over the two treatment periods of Part 2, treatments with epoprostenol AS and epoprostenol GM were administered in the sequence epoprostenol AS/epoprostenol GM or epoprostenol GM/epoprostenol AS, with 10 subjects per sequence as determined by randomization. In part 1 and part 2 of the study, for each treatment period, subjects entered the clinic on day -1. On day 1, according to the randomization scheme, epoprostenol AM or epoprostenol AS in part 1 and epoprostenol AS or epoprostenol GM in part 2, was administered as sequential i.v. infusions of 2, 4, 6, and 8 ng/kg/min for 2 hours (h) each, followed by an observation period of 40 h. On day 2, 24 h after the infusion start, the subjects left the clinic after completion of the scheduled assessments. Subjects returned to the clinic on day 3, 48 h after the infusion start, to complete the assessments of the end of period visit. For study part 1 and part 2, the end of period visit of the last treatment period was considered the end of study (EOS) visit. Throughout the study, safety of the subjects was assessed by means of physical examinations, clinical laboratory tests (hematology, including coagulation screen, and serum chemistry), electrocardiograms, vital signs performed at regular intervals from predose to EOS. Concomitant medications and treatment-emergent adverse events occurring at any time during each treatment period were recorded. Pharmacokinetic and pharmacodynamic measurements were performed at predefined time points from predose to 24 h after infusion start.