title: Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag.
abstract: OBJECTIVE
  Targeting the prostacyclin pathway is an effective treatment option for pulmonary arterial hypertension (PAH). Patients with PAH have a deficiency of prostacyclin and prostacyclin synthase. Selexipag is an orally available and selective prostacyclin receptor (IP receptor) agonist. Selexipag is hydrolyzed to its active metabolite ACT-333679, also a selective and potent agonist at the IP receptor.
  
  
  METHODS
  In this phase I study the pharmacokinetics (PK) and tolerability of single and multiple ascending doses of selexipag were investigated in a double-blind, placebo-controlled manner in 64 healthy male subjects. An additional group of 12 subjects received an open-label dose of selexipag 400 μg in the fasted condition and after a meal.
  
  
  RESULTS
  Maximum plasma concentrations of selexipag and ACT-333679 were reached within 2.5 and 4 h, respectively, with mean half-lives of 0.7-2.3 and 9.4-14.22 h. In the presence of food, exposure to ACT-333679 was decreased by 27 %. The most frequent adverse event was headache. Selexipag was well tolerated up to a single dose of 400 μg and multiple doses of 600 μg following an up-titration step. No relevant treatment-related effects on vital signs, clinical laboratory, and electrocardiogram (ECG) parameters were detected.
  
  
  CONCLUSIONS
  Selexipag exhibits a good tolerability profile and PK properties that warrant further investigation.
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland, priska.kaufmann@actelion.com.
authors: Priska
authors: P
authors: Kaufmann
authors: Kaori
authors: K
authors: Okubo
authors: Shirin
authors: S
authors: Bruderer
authors: Tim
authors: T
authors: Mant
authors: Tetsuhiro
authors: T
authors: Yamada
authors: Jasper
authors: J
authors: Dingemanse
authors: Hideya
authors: H
authors: Mukai
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000085:Acetates / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D044006:Receptors, Epoprostenol / Q000819:agonists*; D055815:Young Adult
chemical_list: D000081:Acetamides; D000085:Acetates; D000959:Antihypertensive Agents; D011719:Pyrazines; D044006:Receptors, Epoprostenol; C523468:selexipag; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid