Abstract 21458: Biocomparability of Two Formulations of Epoprostenol, Epoprostenol for Injection* (ACT-385781A) and Flolan®, via Pharmacokinetic Assessment of Two Primary Metabolites.
Background: Epoprostenol is available for the treatment of pulmonary arterial hypertension as Flolan® (FLO) or Epoprostenol for Injection (EFI). EFI has the same active ingredient (epoprostenol sodium) as the reference product, FLO, but was developed with a change in excipients to improve the stability profiles after reconstitution and dilution. In that context, a study comparing the pharmacokinetics of EFI to the reference product FLO in healthy male subjects was conducted in order to further support the biocomparability of both products.
Methods: Twenty healthy male subjects (mean ± SD age 33.7 ± 8.1 years) were enrolled in an open-label, two-period, crossover, ascending-dose study with a 7-day washout between dosing periods. During each dosing period, the subjects received sequential, 2-hour infusions of either EFI or FLO at 2, 4, 6 and 8ng/kg/min. Because the parent epoprostenol has a very short t1/2 of approximately 6 minutes, plasma pharmacokinetics of EFI and FLO were derived by non-compartmental analysis of the concentration—time profiles of two major metabolites, 6-keto-Prostacyclin F1α (kPF) and 6,15-diketo-13,14-dihydro-Prostacyclin F1α (ddPF).
Results: The plasma concentration—time profiles of EFI and FLO, measured via kPF and ddPF, were virtually superimposable. Concentration values of kPF and ddPF, obtained 2 hours after the end of each infusion rate, were not affected by the formulation administered. The AUC0−∞ geometric means of kPF following administration of EFI and FLO, respectively, were 2021 and 1972 pg.h/mL (90% CI of the ratio = 97, 107), whereas those of ddPF were 665 and 654 pg.h/mL (90% CI of the ratio = 94, 111). The t1/2 values of both metabolites were also not affected by the formulation. Sixteen out of 20 subjects in the EFI group and 19 out of 20 subjects in the FLO group reported treatment-emergent adverse events (TEAEs), the most common of which was headache.
Conclusions: These data show that the EFI and FLO formulations were biocomparable, as measured via the pharmacokinetics of the two major metabolites of epoprostenol, kPF and ddPF, as well as by comparison of their TEAE profiles. *Epoprostenol for Injection is commercialized in the USA under the Brand name Veletri®.
- © 2010 by American Heart Association, Inc.