Skip to main content
SpringerLink
Log in

A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background

Macitentan and its active metabolite, aprocitentan, are non-peptide, potent, dual endothelin receptor antagonists. Macitentan is approved for the treatment of pulmonary arterial hypertension in adults, at a dose of 10 mg/day.

Objective

The objective of this study was to develop a comprehensive population model to describe the pharmacokinetics of macitentan and aprocitentan in healthy adults and adult subjects with pulmonary arterial hypertension.

Methods

Pharmacokinetic data of 452 subjects in nine studies, after single and repeated doses (dose range 0.2–600 mg), were pooled for a non-linear mixed-effects analysis and the assessment of covariates, i.e., body weight, age, sex, race, renal and hepatic impairment, health status (healthy volunteers vs patients with pulmonary arterial hypertension), and formulation (capsules vs tablets) on pharmacokinetic parameters.

Results

The final model was an open one-compartment disposition model, with linear elimination for macitentan and linear formation and elimination for aprocitentan. A semi-mechanistic absorption model described the dose dependency and multiple peaks observed for macitentan. For a female patient with pulmonary arterial hypertension after oral administration at 10 mg, macitentan reached a maximum concentration after 9 h and, following daily dosing, reached steady state after 3 days with a twofold accumulation factor. The apparent volume of distribution was 34 L and clearance was 1.39 L/h. Aprocitentan reached maximum concentration after 51 h and steady state after 9 days, with a 12.5-fold accumulation factor. Body weight, sex, race, renal impairment, health status, and formulation were statistically significant covariates on pharmacokinetic parameters.

Conclusions

The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations. Several covariates significantly influenced the pharmacokinetics of macitentan and aprocitentan, but none was considered clinically relevant.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425–36.

    Article  CAS  Google Scholar 

  2. Sidharta PN, Treiber A, Dingemanse J. Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015;54(5):457–71.

    Article  CAS  Google Scholar 

  3. Dingemanse J, Sidharta PN, Maddrey WC, Rubin LJ, Mickail H. Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf. 2014;13(3):391–405.

    Article  CAS  Google Scholar 

  4. US Food and Drug Administration. Opsumit® (macitentan) prescribing information. 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204410s017lbl.pdf. Accessed 26 Nov 2020.

  5. EMC. Summary of product characteristics: Opsumit (macitentan). 2020. https://www.medicines.org.uk/emc/product/5223/smpc. Accessed 26 Nov 2020.

  6. Atsmon J, Dingemanse J, Shaikevich D, Volokhov I, Sidharta PN. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet. 2013;52(8):685–92.

    Article  CAS  Google Scholar 

  7. Krause A, Zisowsky J, Dingemanse J. Modeling of pharmacokinetics, efficacy, and hemodynamic effects of macitentan in patients with pulmonary arterial hypertension. Pulm Pharmacol Ther. 2018;49:140–6.

    Article  CAS  Google Scholar 

  8. Sidharta PN, van Giersbergen PL, Halabi A, Dingemanse J. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977–84.

    Article  CAS  Google Scholar 

  9. Sidharta PN, van Giersbergen PL, Dingemanse J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol. 2013;53(11):1131–8.

    CAS  PubMed  Google Scholar 

  10. US Food and Drug Administration. Clinical pharmacology and biopharmaceutics review. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf. Accessed 26 Nov 2020.

  11. Bruderer S, Marjason J, Sidharta PN, Dingemanse J. Pharmacokinetics of macitentan in Caucasian and Japanese subjects: the influence of ethnicity and sex. Pharmacology. 2013;91(5–6):331–8.

    Article  CAS  Google Scholar 

  12. Ahn LY, Kim SE, Yi S, et al. Pharmacokinetic–pharmacodynamic relationships of macitentan, a new endothelin receptor antagonist, after multiple dosing in healthy Korean subjects. Am J Cardiovasc Drugs. 2014;14(5):377–85.

    Article  CAS  Google Scholar 

  13. Sidharta PN, Lindegger N, Ulč I, Dingemanse J. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. 2014;54(3):291–300.

    Article  CAS  Google Scholar 

  14. Kummer O, Haschke M, Hammann F, et al. Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan. Eur J Pharm Sci. 2009;38(4):384–8.

    Article  CAS  Google Scholar 

  15. Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ, editors. NONMEM 7.3.0 users guide (1989–2014). Ellicott City: Icon Development Solutions.

  16. R Archive Network. http://cran.r-project.org. Accessed 26 Nov 2020.

  17. de Kanter R, Sidharta PN, Delahaye S, et al. Physiologically-based pharmacokinetic modeling of macitentan: prediction of drug–drug interactions. Clin Pharmacokinet. 2016;55(3):369–80.

    Article  Google Scholar 

  18. US Food and Drug Administration. Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf. Accessed 26 Nov 2020.

  19. US Food and Drug Administration. Guidance for industry: pharmacokinetics in patients with impaired renal function: study design, data analysis, and impact on dosing and labeling. 2010. https://www.fda.gov/downloads/drugs/guidances/ucm204959.pdf. Accessed 26 Nov 2020.

  20. Xu XS, Yuan M, Zhu H, et al. Full covariate modelling approach in population pharmacokinetics: understanding the underlying hypothesis tests and implications of multiplicity. Br J Clin Pharmacol. 2018;84(7):1525–34.

    Article  CAS  Google Scholar 

  21. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51.

    Article  Google Scholar 

  22. Bauer RJ. NONMEM tutorial part II: estimation methods and advanced examples. CPT Pharmacomet Syst Pharmacol. 2019;8(8):538–56.

    Article  CAS  Google Scholar 

  23. Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM. J Pharmacokinet Pharmacodyn. 2008;35(4):401–21.

    Article  Google Scholar 

  24. Volz AK, Dingemanse J, Krause A, Lehr T. Target-mediated population pharmacokinetic modeling of endothelin receptor antagonists. Pharm Res. 2020;37(1):1–12.

    Article  Google Scholar 

  25. Bruderer S, Hopfgartner G, Seiberling M, et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012;42(9):901–10.

    Article  CAS  Google Scholar 

  26. Sidharta PN, Melchior M, Kankam MK, Dingemanse J. Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects. Drug Des Dev Ther. 2019;13:949–64.

    Article  CAS  Google Scholar 

  27. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy

    Roberta Bartolucci & Paolo Magni

  2. Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, Antwerp, Belgium

    Roberta Bartolucci, Anne-Gaëlle Dosne, Juan José Pérez-Ruixo & Italo Poggesi

  3. Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, Allschwil, Switzerland

    Dénes Csonka

Authors
  1. Roberta Bartolucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne-Gaëlle Dosne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dénes Csonka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juan José Pérez-Ruixo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paolo Magni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Italo Poggesi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Italo Poggesi.

Ethics declarations

Authors’ contributions

RB, AGD, DC, JJPR, PM, and IP contributed to the design of the work, the acquisition of the data, the analysis or interpretation of the data, and the preparation of the manuscript. All authors have approved the submitted version and are accountable for it.

Conflicts of interest

Anne-Gaëlle Dosne, Dénes Csonka, Juan José Pérez-Ruixo, and Italo Poggesi were employees and shareholders of Janssen Pharmaceutical Companies at the time this analysis was conducted.

Funding

The clinical studies were supported by research funding from Actelion (currently, a Janssen pharmaceutical company).

Ethics approval

The studies were conducted in accordance with principles for human experimentation as defined in the Declaration of Helsinki and were approved by the human investigational review board of the study center and by the competent authority of the country.

Consent to participate

Informed consent was obtained from each subject before enrollment in the studies, after being advised of the potential risks and benefits, as well as the investigational nature of the studies.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

The NONMEM script of the final model is available as ESM.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2564 kb)

Supplementary file2 (DOCX 20 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bartolucci, R., Dosne, AG., Csonka, D. et al. A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension. Clin Pharmacokinet 60, 1605–1619 (2021). https://doi.org/10.1007/s40262-021-01049-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-021-01049-3

Search

Navigation