title: Absolute oral bioavailability of selexipag, a novel oral prostacyclin IP receptor agonist.
abstract: OBJECTIVE
  The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) versus intravenous (i.v.) formulation of selexipag in healthy subjects.
  
  
  METHODS
  A pilot phase in three healthy male subjects, which preceded the main study, consisted of a single 20-minute i.v. infusion of 50 μg selexipag. Its objectives were to ensure the safety of the i.v. formulation and to select the i.v. dose for the main study. The main study had a randomized, two-way crossover design in 16 healthy male subjects. Subjects received a single oral dose of 400 μg selexipag and a single 80-minute i.v. infusion of 200 μg selexipag.
  
  
  RESULTS
  Three subjects in the pilot and 15 in the main phase completed the study as planned, whereas one subject of the main study withdrew the consent. A geometric mean total body clearance (95% confidence interval (CI)) of 17.9 L/h (15.0-21.5) and a volume of distribution of 11.7 L (10.6-13.0) were determined. The absolute oral bioavailability of selexipag (90% CI) was 49.4% (42.6-57.2). Selexipag was well-tolerated; no adverse event (AE) occurred during the pilot phase, and the main observed AEs were headache, nausea, and vomiting.
  
  
  CONCLUSIONS
  A single i.v. administration of selexipag in healthy subjects was safe and well-tolerated. The bioavailability of selexipag after oral administration is approximately 50%.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. priska.kaufmann@actelion.com.
authors.forename: Priska
authors.initials: P
authors.lastname: Kaufmann
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Noémie
authors.initials: N
authors.lastname: Hurst
authors.affiliation: Biotrial, 7-9 Rue Jean-Louis Bertrand, 35000, Rennes, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Astruc
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000085:Acetates / Q000097:blood; D000284:Administration, Oral; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011719:Pyrazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists*; D055815:Young Adult
chemical_list: D000081:Acetamides; D000085:Acetates; D000959:Antihypertensive Agents; C113936:PTGIR protein, human; D011719:Pyrazines; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C523468:selexipag; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid
keywords: Bioavailability; Pharmacokinetics; Prostacyclin receptor agonist; Selexipag