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

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

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.

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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.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland

    Patricia N. Sidharta & Jasper Dingemanse

Authors
  1. Patricia N. Sidharta
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  2. Jasper Dingemanse
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Corresponding author

Correspondence to Patricia N. Sidharta.

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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.

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Sidharta, P.N., Dingemanse, J. Effect of Multiple-Dose Aprocitentan Administration on the Pharmacokinetics of Midazolam in Healthy Male Subjects. Eur J Drug Metab Pharmacokinet 45, 227–234 (2020). https://doi.org/10.1007/s13318-019-00590-8

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  • DOI: https://doi.org/10.1007/s13318-019-00590-8

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