European Journal of Clinical Pharmacology

, Volume 75, Issue 2, pp 195–205 | Cite as

Interaction potential of the dual orexin receptor antagonist ACT-541468 with CYP3A4 and food: results from two interaction studies

  • Marie-Laure BoofEmail author
  • Abir Alatrach
  • Mike Ufer
  • Jasper Dingemanse
Pharmacokinetics and Disposition



ACT-541468 is a novel dual orexin receptor antagonist (DORA) under development for the treatment of insomnia. In vitro studies suggested a significant role of CYP3A4 in ACT-541468 metabolism and an impact on CYP3A4 activity.


Subsequently, two clinical cross-over studies investigated the victim (n = 14 healthy subjects) and perpetrator (n = 20) potential of 25 mg ACT-541468 with respect to CYP3A4. The effect of food intake on the pharmacokinetics of ACT-541468 was also investigated.


Moderate CYP3A4 inhibition by diltiazem (240 mg/day) increased the Cmax and AUC0–∞ of ACT-541468 by 1.4-fold (90% confidence interval (CI): 1.2–1.6) and 2.4-fold (90% CI: 2.0–2.8), respectively, and prolonged t½ by 80% (90% CI: 60–90) without affecting tmax. Single- and multiple-dose administration of 25 mg ACT-541468 had no impact on the pharmacokinetics of the sensitive substrate midazolam and its main metabolite 1-hydroxy midazolam indicated by 90% CI of the geometric mean ratios of Cmax and AUC within bioequivalence criteria and by an unchanged tmax. After a high-fat high-calorie breakfast, the pharmacokinetic profile of 25 mg ACT-541468 showed a decrease of Cmax by 24% (90% CI: 17–31) and a delay of tmax by approximately 2 h (90% CI: 1.4–2.4), whereas t½ and AUC0–24 remained essentially unchanged. ACT-541468 given alone or in combination with diltiazem, midazolam, or food was safe and well tolerated.


Overall, ACT-541468 has been determined as CYP3A4 substrate but without any perpetrator drug–drug interaction potential regarding CYP3A4 in humans. Food affected ACT-541468 absorption without modifying overall exposure.


ACT-541468 CYP3A4 Food Diltiazem Midazolam Pharmacokinetics 



The authors thank Dr. Atef Halabi and the study team at Clinical Research Services (CRS, Kiel, Germany) for the clinical conduct of both studies, Mariya Antonova and Radka Štěpánová (Aprova s.r.o., Brno, Czech Republic) for statistical analysis of clinical data, Susanne Globig (Department of Preclinical Pharmacokinetics and Metabolism, Idorsia Pharmaceuticals Ltd), and Lena Borkowski (ACC GmbH Analytical Clinical Concepts, Leidersbach, Germany) for the bioanalytical conduct of ACT-541468 and midazolam/1-OH midazolam, respectively.

Compliance with ethical standards

Conflict of interest

Actelion Pharmaceuticals Ltd., the predecessor of Idorsia Pharmaceuticals Ltd., provided funding for this clinical study, as owner of ACT-541468. At the time of the study conduct or reporting, M.-L.B., M.U., and J.D. were full-time employees of Actelion Pharmaceuticals Ltd. They are now full-time employees of Idorsia Pharmaceuticals Ltd., the current owner of ACT-541468. A.A. was an employee of Clinical Research Services Kiel GmbH. There are no other relationships or activities that could appear to have influenced the submitted work. Clinical Research Services Kiel GmbH received financial compensation for the clinical conduct.

Statement of human rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

228_2018_2559_MOESM1_ESM.pdf (11 kb)
Figure S1 Chemical structure of ACT-541468 (PDF 10 kb)
228_2018_2559_MOESM2_ESM.pdf (171 kb)
Figure S2 Arithmetic mean (± SD) (a) trough plasma concentrations of ACT-541468 after multiple-dose administration of ACT-541468 from Day 4 to Day 8, (b) plasma concentration–time profile of ACT-541468 after single- and multiple-dose administration on a linear and semi-logarithmic scale (n = 20) (PDF 170 kb)
228_2018_2559_MOESM3_ESM.pdf (218 kb)
Figure S3 Arithmetic mean (± SD) plasma concentration–time profile of (a) midazolam and (b) 1-OH midazolam after administration of midazolam alone, 1 h after single-dose ACT-541468, and after multiple-dose 25 mg ACT-541468 from time 0 to 24 h post-dose on a linear and semi-logarithmic scale (n = 20) (PDF 217 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyIdorsia Pharmaceuticals LtdAllschwilSwitzerland
  2. 2.Clinical Research Services Kiel GmbHKielGermany

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