Absolute oral bioavailability of selexipag, a novel oral prostacyclin IP receptor agonist

• Published in: European journal of clinical pharmacology Vol. 73; no. 2; pp. 151 - 156
• Main Authors: Kaufmann, Priska, Hurst, Noémie, Astruc, Béatrice, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2017; Springer Nature B.V
• Subjects: Acetamides - adverse effects; Acetamides - blood; Acetamides - pharmacokinetics; Acetates - blood; Administration, Oral; Adult; Antihypertensive Agents - adverse effects; Antihypertensive Agents - blood; Antihypertensive Agents - pharmacokinetics; Bioavailability; Biological Availability; Biomedical and Life Sciences; Biomedicine; Clinical Trial; Clinical trials; Cross-Over Studies; Drug delivery systems; Drug therapy; Humans; Infusions, Intravenous; Male; Pharmacology/Toxicology; Pulmonary hypertension; Pyrazines - adverse effects; Pyrazines - blood; Pyrazines - pharmacokinetics; Receptors, Epoprostenol; Receptors, Prostaglandin - agonists; Young Adult; Bioavailability; Pharmacokinetics; Prostacyclin receptor agonist; Selexipag
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-016-2164-4

Purpose 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. Conclusion 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%.