Poster #004: Absolute Oral Bioavailability of Selexipag, a Novel Oral Prostacyclin IP Receptor Agonist, in Healthy Subjects

摘要

Statement of Purpose, Innovation or Hypothesis: Selexipag is a selective, orally-bioavailable, non-prostanoid agonist at the prostacyclin IP receptor, approved for the treatment of pulmonary arterial hypertension. The active metabolite of selexipag, ACT-333679, is approximately 37-fold as potent as selexipag in vitro and is present at 3- to 4-fold higher levels than the parent drug in humans following oral administration. Therefore, ACT-333679 is considered the major contributor to the efficacy of selexipag. The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) vs intravenous (IV) formulation of selexipag in healthy male subjects. Description of Methods and Materials: A pilot phase in three subjects, which preceded the main study, consisted of a single 20-min IV infusion of 50 μg selexipag. Its objectives were to ensure safety of the IV formulation and to select the IV dose for the main study. The main study was a randomized, two-way, cross-over study in 16 healthy male subjects. Subjects received a single, oral dose of 400 μg selexipag and a single 80-min IV infusion of 200 μg selexipag. Pharmacoki-netic parameters of selexipag and ACT-333679 were determined by noncompartmental analyses. Tolerability and safety were assessed throughout the study. Data and Results: Eighteen subjects completed the study as planned and one subject of the main phase withdrew consent prematurely. Selexipag administered by both routes was well tolerated; the main observed adverse event (AE) was headache reported by 11 subjects (68.8%). All AEs, except for two cases of headache, were of mild intensity. The absolute oral bioavailabil-ity of selexipag was 49.4% (90% CI: 42.6-57.2). A geometric mean total body clearance of 18 L/h (95% CI: 15-21) and volume of distribution of 12 L (95% CI: 11-13) were determined after IV administration. Following oral treatment, exposure to ACT-333679 was 3.4-fold higher than to selexipag, whereas after IV administration, exposure to ACT-333679 was 1.3-fold higher than to selexipag. Interpretation, Conclusion or Significance: Selexipag appears to undergo first-pass metabolism following oral administration.