SpringerLink
Log in

Biocomparison Study of Adult and Paediatric Dose Strengths of the Prostacyclin Receptor Agonist Selexipag

  • Short Communication
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and objectives

Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg selexipag (Treatment A) vs. 4 paediatric tablets of 50 µg (Treatment B) in healthy adult male subjects.

Methods

This was an open-label, randomized, two-treatment, two-period, crossover biocomparison study. Bioequivalence criteria were explored and safety variables (vital signs, electrocardiogram, and laboratory parameters) were assessed.

Results

The exploratory analysis showed that the 90% confidence intervals of geometric mean ratio (Treatment B/Treatment A) for maximum plasma concentration (C max), area under the plasma concentration–time curve from zero to infinity (AUC0–∞) of ACT-333679, as well as AUC0–∞ of selexipag, were within the bioequivalence interval (0.80, 1.25). In addition, no relevant difference in C max for selexipag between the two treatments can be concluded. Single oral dose administration of 200 µg selexipag as one tablet of 200 µg or four tablets of 50 µg was well tolerated.

Conclusions

Pharmacokinetic characteristics of selexipag and its metabolite ACT-333679 following administration of one adult tablet of 200 µg selexipag and four paediatric tablets of 50 µg selexipag were comparable.

Trial registration

ClinicalTrials.gov identifier: NCT02745860.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655–65.

    Article  CAS  PubMed  Google Scholar 

  2. Wort SJ, Woods M, Warner TD, Evans TW, Mitchell JA. Cyclooxygenase-2 acts as an endogenous brake on endothelin-1 release by human pulmonary artery smooth muscle cells: implications for pulmonary hypertension. Mol Pharmacol. 2002;62(5):1147–53.

    Article  CAS  PubMed  Google Scholar 

  3. Dorris SL, Peebles RS Jr. PGI2 as a regulator of inflammatory diseases. Mediators Inflamm. 2012;2012:926968.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kuwano K, Hashino A, Asaki T, Hamamoto T, Yamada T, Okubo K, et al. 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. 2007;322(3):1181–8.

    Article  CAS  PubMed  Google Scholar 

  5. EMA. Selexipag (UPTRAVI): annex I, summary of product characteristics. February 2017.

  6. FDA. Highlights of Prescribing Information: Uptravi® (selexipag) tablets, for oral use. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207947s000lbl.pdf. December 2015.

  7. Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373(26):2522–33.

    Article  CAS  PubMed  Google Scholar 

  8. Baldoni D, Bruderer S, Muhsen N, Dingemanse J. 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 s. 2015;53(9):788–98.

    Article  CAS  Google Scholar 

  9. Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J. 2011;37(3):665–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. Pediatric pulmonary hypertension: guidelines from the american heart association and american thoracic society. Circulation. 2015;132(21):2037–99.

    Article  PubMed  Google Scholar 

  11. Hansmann G, Apitz C. Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016;102 Suppl 2:ii67–85.

  12. FDA. Guidance for industry: E11 Clinical investigation of medicinal products in the pediatric population. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073143.pdf. December 2000.

  13. FDA. Draft Guidance for industry: General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products. https://www.fda.gov/downloads/drugs/guidances/ucm425885.pdf. December 2014.

  14. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker; 1982.

    Google Scholar 

  15. Kaufmann P, Niglis S, Bruderer S, Segrestaa J, Aanismaa P, Halabi A, et al. 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. 2015;80(4):670–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. FDA. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations. http://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf. March 2003, Revision 1.

  17. EMA. Committee for medicinal products for human use: Guideline on the investigation of bioequivalence. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. January 2010.

  18. Bruderer S, Hurst N, Kaufmann P, Dingemanse J. 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. 2014;94(3–4):148–56.

    Article  CAS  PubMed  Google Scholar 

  19. Kaufmann P, Okubo K, Bruderer S, Mant T, Yamada T, Dingemanse J, et al. Pharmacokinetics and Tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs. 2015;15(3):195–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Matalova P, Urbanek K, Anzenbacher P. Specific features of pharmacokinetics in children. Drug Metab Rev. 2016;48(1):70–9.

    Article  CAS  PubMed  Google Scholar 

  21. Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther. 2008;118(2):250–67.

    Article  CAS  PubMed  Google Scholar 

  22. Hines RN. Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children. Int J Pharm. 2013;452(1–2):3–7.

    Article  CAS  PubMed  Google Scholar 

  23. Song G, Sun X, Hines RN, McCarver DG, Lake BG, Osimitz TG, et al. Determination of human hepatic CYP2C8 and CYP1A2 Age-dependent expression to support human health risk assessment for early ages. Drug Metab Dispos. 2017;45(5):468–75.

    Article  CAS  PubMed  Google Scholar 

  24. Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. 2009;37(9):1819–25.

    Article  CAS  PubMed  Google Scholar 

  25. Shi D, Yang D, Prinssen EP, Davies BE, Yan B. Surge in expression of carboxylesterase 1 during the post-neonatal stage enables a rapid gain of the capacity to activate the anti-influenza prodrug oseltamivir. J Infect Dis. 2011;203(7):937–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol. 2009;77(2):238–47.

    Article  CAS  PubMed  Google Scholar 

  27. Strassburg CP, Strassburg A, Kneip S, Barut A, Tukey RH, Rodeck B, et al. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut. 2002;50(2):259–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oo C, Hill G, Dorr A, Liu B, Boellner S, Ward P. Pharmacokinetics of anti-influenza prodrug oseltamivir in children aged 1-5 years. Eur J Clin Pharmacol. 2003;59(5–6):411–5.

    Article  CAS  PubMed  Google Scholar 

  29. Batchelor HK, Marriott JF. Formulations for children: problems and solutions. Br J Clin Pharmacol. 2013;79(3):405–18.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Susanne Globig for the bioanalytical conduct and the CEPHA team for clinical conduct.

Author contributions

Performed the study design: MB, SB, and JD. Performed data analysis: MB and SB. Wrote or contributed in the writing of the paper: MB, SB, IU, and JD.

Author information

Authors and Affiliations

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

    Margaux Boehler, Shirin Bruderer & Jasper Dingemanse

  2. CEPHA s.r.o., Komenského 19, 323 00, Pilsen, Czech Republic

    Ivan Ulč

Authors
  1. Margaux Boehler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shirin Bruderer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivan Ulč
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jasper Dingemanse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margaux Boehler.

Ethics declarations

Funding

This study was sponsored by Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.

Conflict of interest

MB, SB, and JD are current employees of Actelion Pharmaceuticals Ltd. IU is a current employee of CEPHA s.r.o.

Ethics approval

All procedures in this study were in accordance with the 1964 Helsinki Declaration (and its amendments), and the independent Ethics Committee (Ethics Committee of CEPHA, Pilsen, Czech Republic) approved the study.

Informed consent

Written informed consent was obtained from all subjects participating in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 102 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boehler, M., Bruderer, S., Ulč, I. et al. Biocomparison Study of Adult and Paediatric Dose Strengths of the Prostacyclin Receptor Agonist Selexipag. Eur J Drug Metab Pharmacokinet 43, 115–120 (2018). https://doi.org/10.1007/s13318-017-0424-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-017-0424-z

Search

Navigation