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

  • Clinical Trial
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Abstract

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%.

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References

  1. O'Grady J, Warrington S, Moti MJ et al (1980) Effects of intravenous infusion of prostacyclin (PGI2) in man. Prostaglandins 19(2):319–332

    Article  PubMed  Google Scholar 

  2. Christman BW (1998) Lipid mediator dysregulation in primary pulmonary hypertension. Chest 114(3 Suppl):205S–207S

    Article  CAS  PubMed  Google Scholar 

  3. Tuder RM, Cool CD, Geraci MW et al (1999) Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159(6):1925–1932

    Article  CAS  PubMed  Google Scholar 

  4. Barst RJ (1997) Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin. Heart 77(4):299–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Barst RJ, Rubin LJ, Long WA et al (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334(5):296–301

    Article  CAS  PubMed  Google Scholar 

  6. Galie N, Torbicki A, Barst R et al (2004) Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The task force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Eur Heart J 25(24):2243–2278

    Article  PubMed  Google Scholar 

  7. Simonneau G, Torbicki A, Hoeper MM et al (2012) Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 40(4):874–880

    Article  CAS  PubMed  Google Scholar 

  8. Sitbon O, Channick R, Chin KM et al (2015) Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 373(26):2522–2533

    Article  CAS  PubMed  Google Scholar 

  9. Kaufmann P, Niglis S, Bruderer S et al (2015) Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects. Br J Clin Pharmacol 80(4):670–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kaufmann P, Okubo K, Bruderer S et al (2015) Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs 15(3):195–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. UPTRAVI® (selexipag) (2015) Tablets for oral use, prescribing information, US package insert. Actelion Pharmaceuticals US Inc, South San Francisco

    Google Scholar 

  12. Bruderer S, Hurst N, Kaufmann P, Dingemanse J (2014) Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects. Pharmacology 94(3–4):148–156

    Article  CAS  PubMed  Google Scholar 

  13. Kaufmann P, Niglis S, Bruderer S et al (2015) Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects. Br J Clin Pharmacol 80:670–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kuwano K, Hashino A, Asaki T et al (2007) 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 322(3):1181–1188

    Article  CAS  PubMed  Google Scholar 

  15. Morrison K, Ernst R, Hess P, Studer R, Clozel M (2010) Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther 335(1):249–255

    Article  CAS  PubMed  Google Scholar 

  16. Baldoni D, Bruderer S, Muhsen N, Dingemanse J (2015) Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study. Int J Clin Pharmacol Ther 53(9):788–798

    Article  CAS  PubMed  Google Scholar 

  17. Hoch M, Darpo B, Remenova T et al (2015) A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist. Drug Des Devel Ther 9:175–185

    PubMed  Google Scholar 

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Acknowledgements

The authors wish to express their thanks to Caroline Averius and Sandrine Gioria for project management, Beya Khouildi for monitoring, Hélène Tribodet from Biotrial, Rennes, France, for statistical analysis of clinical and PK data, and Susanne Globig and the staff of Preclinical PK and Metabolism (Actelion Pharmaceuticals Ltd) for the bioanalytical conduct.

Contributions of authors

All authors were involved in the data collection, analysis and/or interpretation, critically revised the manuscript, and approved the final version for publication.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Priska Kaufmann, Noémie Hurst & Jasper Dingemanse

  2. Biotrial, 7-9 Rue Jean-Louis Bertrand, 35000, Rennes, France

    Béatrice Astruc

Authors
  1. Priska Kaufmann
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  2. Noémie Hurst
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  3. Béatrice Astruc
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  4. Jasper Dingemanse
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Corresponding author

Correspondence to Priska Kaufmann.

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Conflicts of interest

At the time of study conduct and reporting, Priska Kaufmann, Noémie Hurst, and Jasper Dingemanse were employees of and received stock options of Actelion Pharmaceuticals Ltd. Béatrice Astruc is an employee of Biotrial, which conducted the study.

Ethical statement

The protocol was approved by the Research Ethics Committee (Comité de Protection des Personnes Ouest VI, Brest, France). Written informed consent was obtained from all subjects. The study was conducted in full compliance with the principles and ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards and also with laws and regulations of France, where the research study was conducted. Prior to starting any activities the French Health Authority Agence National de Sécurité du Médicament et des Produits de Santé (ANSM) reviewed and approved the study.

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Kaufmann, P., Hurst, N., Astruc, B. et al. Absolute oral bioavailability of selexipag, a novel oral prostacyclin IP receptor agonist. Eur J Clin Pharmacol 73, 151–156 (2017). https://doi.org/10.1007/s00228-016-2164-4

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  • DOI: https://doi.org/10.1007/s00228-016-2164-4

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