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Epoprostentol with Expanded Stability has the Same Pharmacokinetic and Pharmacodynamic Profiles as Epoprostenol in Healthy Subjects

L. Nicolas

M. Gutierrez

L. Galitz

J. Dingemanse

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Conference: 2011 PH Professional Network Symposium

Release Date: 09.22.2011

Presentation Type: Abstracts

L. Nicolas, PhD;1 M. Gutierrez, PhD;1 L. Galitz, MD;2 J. Dingemanse, PhD1
1.Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
2.Cetero Research, Miami, FL, USA

RATIONALE: Epoprostenol with expanded stability (Veletri®) is available for the treatment of pulmonary arterial hypertension and contains the same active ingredient (epoprostenol sodium) as epoprostenol (Flolan®), but differs with regard to the excipients. This change in excipients improves the stability after reconstitution and dilution of epoprostenol expanded stability compared with epoprostenol. This study compared the pharmacokinetics and pharmacodynamics of the two formulations in healthy males.

METHODS: Twenty subjects were enrolled in this open-label, two-period, two-treatment, crossover, ascending dose study. During each period epoprostenol expanded stability or epoprostenol was administered as sequential i.v. infusions of 2, 4, 6, and 8 ng/kg/min for 2 h each. Since epoprostenol sodium has a very short half-life (t1/2), the pharmacokinetics of epoprostenol expanded stability and epoprostenol were assessed via the concentration versus time profiles of 2 primary metabolites, i.e., 6-keto-Prostacyclin F1α (kPF) and 6,15-diketo-13,14-dihydro-Prostacyclin F1α (ddPF). Hemodynamic variables, cardiac output (CO), cardiac index (CI), and heart rate (HR) were assessed using echocardiography.

RESULTS: The plasma concentration versus time profiles of epoprostenol and epoprostenol with expanded stability, measured via kPF and ddPF, were virtually superimposable. Concentration values of kPF and ddPF, obtained 2 h after the end of each infusion, were not affected by the formulation administered. Following administration of epoprostenol expanded stability or epoprostenol, the total area under the curve (AUC0-∞) geometric means of kPF were 2021 pg.h/mL and 1972 pg.h/mL, those of ddPF were 665 pg.h/mL and 654 pg.h/mL. The t1/2 values of both metabolites were also not affected by the formulation: t1/2 for kPF were 0.25 h and 0.22 h and for ddPF were 0.32 h and 0.34 h following epoprostenol expanded stability or epoprostenol administration, respectively. Similar increases in CO, CI, and HR during epoprostenol expanded stability or epoprostenol infusion were observed, with maximum values attained between 6-8 h from start of administration. Average maximum increases from baseline after 8 h of infusion were approximately 1 L/min for CO, 0.6 L/min/m2 for CI, and 12-16 bpm for HR. This translates to an approximate 30% increase from baseline after 8 hours infusion in both CO and CI with either formulation, and increases in HR of 19% for epoprostenol expanded stability and 27% for epoprostenol. Sixteen of 18 subjects following epoprostenol expanded stability and 19 of 20 subjects following epoprostenol reported treatment-emergent adverse events, headache being the most common.

CONCLUSION: Overall, epoprostenol expanded stability and epoprostenol have similar pharmacokinetic, hemodynamic, safety, and tolerability profiles.