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Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug–Drug Interactions

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Abstract

Introduction

Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577.

Methods

A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro.

Results

The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan–drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH.

Conclusion

This example of the application of PBPK modeling to predict drug–drug interactions was used to support the labeling of macitentan (Opsumit).

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References

  1. Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PloS One. 2012;7:e47662.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327:736–45.

    Article  CAS  PubMed  Google Scholar 

  3. Treiber A, Aanismaa P, de Kanter R, Delahaye S, Treher M, Hess P, et al. Macitentan does not interfere with hepatic bile salt transport. J Pharmacol Exp Ther. 2014;350:130–43.

    Article  PubMed  Google Scholar 

  4. Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60–72.

    Article  PubMed  Google Scholar 

  5. Cicalini S, Chinello P, Petrosillo N. HIV infection and pulmonary arterial hypertension. Expert Rev Respir Med. 2011;5:257–66.

    Article  PubMed  Google Scholar 

  6. Jones H, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacomet Syst Pharmacol. 2013;2:1–12.

    Google Scholar 

  7. Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet. 2009;24:53–75.

    Article  CAS  PubMed  Google Scholar 

  8. Jones HM, Gardner IB, Watson KJ. Modelling and PBPK simulation in drug discovery. AAPS J. 2009;11:155–66.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Edginton AN, Theil FP, Schmitt W, Willmann S. Whole body physiologically-based pharmacokinetic models: their use in clinical drug development. Expert Opin Drug Metab Toxicol. 2008;4:1143–52.

    Article  CAS  PubMed  Google Scholar 

  10. Rowland M, Peck C, Tucker G. Physiologically-based pharmacokinetics in drug development and regulatory science. Ann Rev Pharmacol Toxicol. 2011;51:45–73.

    Article  CAS  Google Scholar 

  11. Huang SM, Rowland M. The role of physiologically based pharmacokinetic modeling in regulatory review. Clin Pharmacol Ther. 2012;91:542–9.

    Article  CAS  PubMed  Google Scholar 

  12. Sinha V, Zhao P, Huang SM, Zineh I. Physiologically based pharmacokinetic modeling: from regulatory science to regulatory policy. Clin Pharmacol Ther. 2014;95:478–80.

    Article  CAS  PubMed  Google Scholar 

  13. Opsumit (macitentan): summary of product characteristics. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002697/WC500160899.pdf. Accessed 21 July 2015.

  14. 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;52:685–92.

    Article  CAS  PubMed  Google Scholar 

  15. Bruderer S, Aanismaa P, Homery MC, Hausler S, Landskroner K, Sidharta PN, et al. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14:68–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Sidharta PN, van Giersbergen PL, Wolzt M, Dingemanse J. Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects. Br J Clin Pharmacol. 2014;78:1035–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Sidharta PN, Dietrich H, Dingemanse J. Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Clin Drug Investig. 2014;34:545–52.

    Article  CAS  PubMed  Google Scholar 

  18. van Giersbergen PL, Gnerre C, Treiber A, Dingemanse J, Meyer UA. Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor. Eur J Pharmacol. 2002;450:115–21.

    Article  PubMed  Google Scholar 

  19. Proctor N, Tucker G, Rostami-Hodjegan A. Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica. 2004;34:151–78.

    Article  CAS  PubMed  Google Scholar 

  20. Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta PN, Treiber A, et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012;42:901–10.

    Article  CAS  PubMed  Google Scholar 

  21. Center for Drug Evaluation and Research. Application number 204410Orig1s000. Clinical pharmacology and biopharmaceutics review(s). 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf. Accessed 21 July 2015.

  22. Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A. Prediction of intestinal first-pass drug metabolism. Curr Drug Metab. 2007;8:676–84.

    Article  CAS  PubMed  Google Scholar 

  23. Pang KS, Chow EC. Commentary: theoretical predictions of flow effects on intestinal and systemic availability in physiologically based pharmacokinetic intestine models: the traditional model, segregated flow model, and QGut model. Drug Metab Dispos. 2012;40:1869–77.

    Article  CAS  PubMed  Google Scholar 

  24. Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95:1238–57.

    Article  CAS  PubMed  Google Scholar 

  25. Rowland M, Tozer T. Metabolite kinetics, Chap 21. In: Clinical pharmacokinetics: concepts and applications. 3rd ed. Media, PA: Lippincott Williams & Wilkins; 1994. p. 372.

  26. 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;53:1131–8.

    CAS  PubMed  Google Scholar 

  27. Wagner C, Pan Y, Hsu V, Grillo JA, Zhang L, Reynolds KS, et al. Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration. Clin Pharmacokinet. 2015;54:117–27.

    Article  CAS  PubMed  Google Scholar 

  28. Darwich AS, Neuhoff S, Jamei M, Rostami-Hodjegan A. Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the “Advanced Dissolution, Absorption, Metabolism (ADAM)” model. Curr Drug Metab. 2010;11:716–29.

    Article  CAS  PubMed  Google Scholar 

  29. Zisowsky J, Sidharta P, Krause A, Dingemanse J. Pharmacokinetic/pharmacodynamic analyses in SERAPHIN, a randomized, controlled study of macitentan in patients with pulmonary arterial hypertension. Clin Pharmacol Drug Dev. 2013;2:S29.

    Google Scholar 

  30. Zientek MA, Youdim K. Reaction phenotyping: advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes. Drug Metab Dispos. 2015;43:163–81.

    Article  PubMed  Google Scholar 

  31. Tsamandouras N, Rostami-Hodjegan A, Aarons L. Combining the “bottom-up” and “top-down” approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data. Br J Clin Pharmacol. 2013;79:48–55.

    Article  PubMed Central  Google Scholar 

  32. Zhao P, Ragueneau-Majlessi I, Zhang L, Strong JM, Reynolds KS, Levy RH, et al. Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole: a simulation study. J Clin Pharmacol. 2009;49:351–9.

    Article  CAS  PubMed  Google Scholar 

  33. Opsumit (macitentan): US prescribing information. 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204410s003lbl.pdf. Accessed 21 July 2015.

  34. Australian Public Assessment Report for macitentan. 2014. http://www.tga.gov.au/file/5941/download. Accessed 21 July 2015.

  35. Baxter JG, Brass C, Schentag JJ, Slaughter RL. Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs. J Pharm Sci. 1986;75:443–7.

    Article  CAS  PubMed  Google Scholar 

  36. Kummer O, Haschke M, Hammann F, Bodmer M, Bruderer S, Regnault Y, et al. Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan. Eur J Pharm Sci. 2009;38:384–8.

    Article  CAS  PubMed  Google Scholar 

  37. Bruderer S, Marjason J, Sidharta PN, Dingemanse J. Pharmacokinetics of macitentan in caucasian and Japanese subjects: the influence of ethnicity and sex. Pharmacology. 2013;91:331–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Fabienne Drouet, Julia Khobzaoui and Swen Seeland for their contributions to the in vitro studies, and Makda Fisseha for help in preparing the manuscript.

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Authors and Affiliations

  1. Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Ruben de Kanter, Stéphane Delahaye, Carmela Gnerre, Jerome Segrestaa, Christopher Kohl & Alexander Treiber

  2. Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Patricia N. Sidharta

  3. Preformulation and Preclinical Galenics, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Stephan Buchmann

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  1. Ruben de Kanter
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  2. Patricia N. Sidharta
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  8. Alexander Treiber
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Corresponding author

Correspondence to Ruben de Kanter.

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Funding

This study was funded by Actelion Pharmaceuticals Ltd.

Conflicts of interest

Ruben de Kanter, Patricia N. Sidharta, Stéphane Delahaye, Carmela Gnerre, Jerome Segrestaa, Stephan Buchmann, Christopher Kohl and Alexander Treiber are employees of Actelion Pharmaceuticals Ltd and may receive stock or stock options as part of their compensation.

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de Kanter, R., Sidharta, P.N., Delahaye, S. et al. Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug–Drug Interactions. Clin Pharmacokinet 55, 369–380 (2016). https://doi.org/10.1007/s40262-015-0322-y

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