Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats, dogs and monkeys

Abstract

1. This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs.

2. After oral administration of [¹⁴C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90% of the dose, mainly in the faeces. Biliary excretion was the major elimination pathway for [¹⁴C]MRE-269 as well as [¹⁴C]selexipag, while renal elimination was of little importance. [¹⁴C]Selexipag-related radioactivity was secreted into the milk in lactating rats.

3. Plasma was analysed for total radioactivity, selexipag and MRE-269 in rats and monkeys. Selexipag was negligible in rat plasma due to extensive metabolism, and MRE-269 was present in rat and monkey plasma. A species difference was clearly evident when selexipag was incubated in rat, dog and monkey plasma.

4. Total radioactivity was rapidly distributed to tissues. The highest concentrations were found in the bile duct and liver without significant accumulation or persistence, while there was limited melanin-associated binding, penetration of the blood–brain barrier and placental transfer of drug-related materials.

Keywords:

• Distribution
• excretion
• hydrolysis
• mass balance
• prostacyclin receptor agonist
• pharmacokinetics
• selexipag

Acknowledgements

We thank Mr. R.A. Hoey of Charles River Laboratories, Scotland, UK, Mr. P. Fernyhough of Covance Laboratories Ltd, North Yorkshire, UK, Jérôme Segrestaa, PhD, and Swen Seeland, PhD of Actelion Pharmaceuticals Ltd, and Kazuhiro Seya of Sekisui Medical Co., Ltd, Ibaraki, Japan, for their dedication and experimental contributions, and Dr. Gerald E. Smyth, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, for his help with the manuscript.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.