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A pharmacokinetic drug–drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Purpose

In vitro data showed that selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration (C max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4.

Methods

This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5 mg midazolam alone (treatment A) or on top of steady-state selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600 μg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis.

Results

The C max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1-hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1-hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, selexipag, and the combination was safe and well tolerated.

Conclusion

Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with selexipag.

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Acknowledgements

This study was sponsored by Actelion Pharmaceuticals Ltd., Allschwil, Switzerland. The authors thank Radka Štěpánová (Aprova s.r.o., Brno, Czech Republic) for statistical analysis of clinical data and Susanne Globig (Department of Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd) for the bioanalytical conduct.

Author information

Authors and Affiliations

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

    Pierre-Eric Juif, Margaux Boehler, Shirin Bruderer & Jasper Dingemanse

  2. Eurofins Optimed, 1 rue des Essarts, 38610, Gieres, France

    Yves Donazzolo

Authors
  1. Pierre-Eric Juif
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  2. Margaux Boehler
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  3. Yves Donazzolo
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  4. Shirin Bruderer
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  5. Jasper Dingemanse
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Corresponding author

Correspondence to Pierre-Eric Juif.

Ethics declarations

The French Ethics Committee (Comité de Protection des Personnes, Sud-Est IV, Lyon, France) reviewed and approved the study protocol and any material provided to the study participants. This study was conducted in full compliance with the principles of the Declaration of Helsinki.

Competing interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any third party organization for the submitted work and no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years. PEJ, MB, SB, and JD are full-time employees of Actelion Pharmaceuticals Ltd. PEJ, SB, and JD possess stock options. YD was employed by Eurofins Optimed (France) in the previous 3 years.

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Juif, PE., Boehler, M., Donazzolo, Y. et al. A pharmacokinetic drug–drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. Eur J Clin Pharmacol 73, 1121–1128 (2017). https://doi.org/10.1007/s00228-017-2282-7

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  • DOI: https://doi.org/10.1007/s00228-017-2282-7

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