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Effect of Multiple-Dose Aprocitentan Administration on the Pharmacokinetics of Midazolam in Healthy Male Subjects

  • Patricia N. SidhartaEmail author
  • Jasper Dingemanse
Original Research Article
  • 18 Downloads

Abstract

Background

Aprocitentan is an orally active dual endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug–drug interaction potential of aprocitentan on cytochrome P450 (CYP) 3A enzymes was investigated in this open-label, two-treatment single-sequence study.

Objectives

The primary and main secondary objectives were to study the pharmacokinetics of midazolam in the absence and presence of aprocitentan and the safety and tolerability of combined administration, respectively.

Methods

Nineteen healthy male subjects received a single dose of 8 mg midazolam. Thereafter, they started aprocitentan treatment (loading dose of 150 mg followed by 50 mg once daily) and received another single dose of midazolam with aprocitentan at steady state. Pharmacokinetics and tolerability of midazolam and its metabolite 1-hydroxy midazolam were assessed over 24 h after each midazolam administration.

Results

At steady state, aprocitentan did not affect the area under the plasma concentration-time curve and maximum plasma concentration (Cmax) of midazolam and 1-hydroxy midazolam, with a geometric means ratio (GMR) of midazolam + aprocitentan/midazolam alone close to 1 and 90% confidence intervals (CI) between 0.88 and 1.23. For the Cmax of 1-hydroxy midazolam the GMR (90% CI) was 0.86 (0.70–1.05). Somnolence, a known side-effect of midazolam, was reported as the most frequent adverse event. There were no relevant differences in tolerability parameters between treatments.

Conclusion

Aprocitentan does not alter the pharmacokinetics of midazolam to a clinically relevant extent and was well tolerated when administered concomitantly. Therefore, aprocitentan can be administered together with drugs that are substrates of CYP3A without dose adjustments.

Notes

Acknowledgements

This study was conducted by Biotrial Inc, Newark, NJ, USA. The authors would like to thank Michael Dobrow, DO who served as principal investigator and JP Jones, PhD who was the Clinical Pharmacologist involved in this study.

Compliance with Ethical Standards

Funding

This study was funded by Actelion Pharmaceuticals Ltd.

Conflicts of Interest

PNS and JD are current employees of Idorsia Pharmaceuticals Ltd and former employees of Actelion Pharmaceuticals Ltd, the company that funded the study. The authors report no other conflict of interest in this work.

Ethics Approval

The study (NCT02841761) followed the principles of the Declaration of Helsinki, its amendments, and good clinical practice, and the protocol was approved by an Independent Review Board (Integreview IRB, Austin, TX, USA).

Informed Consent

All subjects provided written informed consent prior to screening.

References

  1. 1.
    Trensz F, Bortolamiol C, Kramberg M, Wanner D, Hadana H, Rey M, Strasser DS, Delahaye S, Hess P, Vezzali E, Mentzel U, Menard J, Clozel M, Iglarz M. Pharmacological characterization of aprocitentan, a dual endothelin receptor antagonist, alone and in combination with blockers of the renin angiotensin system, in two models of experimental hypertension. J Pharmacol Exp Ther. 2019;368(3):462–73.CrossRefGoogle Scholar
  2. 2.
    Dhaun N, Webb DJ. Endothelins in cardiovascular biology and therapeutics. Nat Rev Cardiol. 2019;16(8):491–502.CrossRefGoogle Scholar
  3. 3.
    Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. 1994;344(8926):852–4.CrossRefGoogle Scholar
  4. 4.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.CrossRefGoogle Scholar
  5. 5.
    Jagannathan R, Patel SA, Ali MK, Narayan KMV. Global updates on cardiovascular disease mortality trends and attribution of traditional risk factors. Curr Diab Rep. 2019;19(7):44.CrossRefGoogle Scholar
  6. 6.
    Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269–324.CrossRefGoogle Scholar
  7. 7.
    Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I, Group ESCSD. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–104.CrossRefGoogle Scholar
  8. 8.
    FDA (2018) U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: hypertension: conducting studies of drugs to treat patients on a background of multiple antihypertensive drugs. Silver Spring, MD, USA. Draft Guidance, July, 2018.Google Scholar
  9. 9.
    Elijovich F, Laffer CL, Amador E, Gavras H, Bresnahan MR, Schiffrin EL. Regulation of plasma endothelin by salt in salt-sensitive hypertension. Circulation. 2001;103(2):263–8.CrossRefGoogle Scholar
  10. 10.
    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 Devel Ther. 2019;13:949–64.CrossRefGoogle Scholar
  11. 11.
    Sidharta PN, Fischer H, Delahaye S, Dingemanse J. Absorption, distribution, metabolism and excretion of aprocitentan, a dual endothelin receptor antagonist, in humans (Abstract). Clin Pharmacol Drug Dev. 2019;8(S1):14–5.Google Scholar
  12. 12.
    EMA (2012) European Medicines Agency (EMA) – Committee for Medicinal Products for Human use (CHMP): Guideline on the investigation of drug interactions. (CPMP/EWP/560/95/Rev.1 Corr. 2). London, UK. 21 June 2012.Google Scholar
  13. 13.
    FDA (2017) U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Guidance for industry: clinical drug interaction studies- study design, data analysis, and clinical implications. Silver Spring, MD.Google Scholar
  14. 14.
    Bornemann LD, Min BH, Crews T, Rees MM, Blumenthal HP, Colburn WA, Patel IH. Dose dependent pharmacokinetics of midazolam. Eur J Clin Pharmacol. 1985;29(1):91–5.CrossRefGoogle Scholar
  15. 15.
    Juif PE, Boehler M, Donazzolo Y, Bruderer S, Dingemanse J. A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. Eur J Clin Pharmacol. 2017;73(9):1121–8.CrossRefGoogle Scholar
  16. 16.
    FDA (2017) U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Guidance for Industry. Silver Spring, MD: December 2017.Google Scholar
  17. 17.
    EMA (2010) European Medicines Agency (EMA) – Committee for Medicinal Products for Human use (CHMP): Guideline on the investigation of bioequivalence. (CPMP/EWP/QWP/1401/98 Rev.1 Corr). London, UK. 01 August 2010.Google Scholar
  18. 18.
    Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–41.CrossRefGoogle Scholar
  19. 19.
    Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;55(5):481–5.CrossRefGoogle Scholar
  20. 20.
    Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O’Mara EM Jr, Hall SD. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther. 1998;64(2):133–43.CrossRefGoogle Scholar
  21. 21.
    Bjorkhem-Bergman L, Backstrom T, Nylen H, Ronquist-Nii Y, Bredberg E, Andersson TB, Bertilsson L, Diczfalusy U. Comparison of endogenous 4beta-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. Drug Metab Dispos. 2013;41(8):1488–93.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyIdorsia Pharmaceuticals LtdAllschwilSwitzerland

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