Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag

• Published in: American Journal of Cardiovascular Drugs Vol. 15; no. 3; pp. 195 - 203
• Main Authors: Kaufmann, Priska, Okubo, Kaori, Bruderer, Shirin, Mant, Tim, Yamada, Tetsuhiro, Dingemanse, Jasper, Mukai, Hideya
• Format: Journal Article
• Language: English
• Published: Cham Springer Science and Business Media LLC 01.06.2015; Springer International Publishing; Springer Nature B.V
• Subjects: Acetamides; Acetamides - administration & dosage; Acetamides - adverse effects; Acetamides - pharmacokinetics; Acetates; Acetates - pharmacokinetics; Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - adverse effects; Antihypertensive Agents - pharmacokinetics; Cardiology; Cardiology and Cardiovascular Medicine; Dose-Response Relationship, Drug; Double-Blind Method; Food-Drug Interactions; Half-Life; Humans; Male; Medicine; Medicine & Public Health; Original; Original Research Article; Pharmacology (medical); Pharmacology/Toxicology; Pharmacotherapy; Pyrazines; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacokinetics; Receptors, Epoprostenol; Receptors, Epoprostenol - agonists; Young Adult; Treprostinil; Epoprostenol; Healthy Male Subject; Single Ascend Dose; Pulmonary Arterial Hypertension
• ISSN: 1175-3277; 1179-187X
• DOI: 10.1007/s40256-015-0117-4

Purpose 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. Conclusion Selexipag exhibits a good tolerability profile and PK properties that warrant further investigation.