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Effect of Liver Cirrhosis on the Pharmacokinetics, Metabolism, and Tolerability of Daridorexant, A Novel Dual Orexin Receptor Antagonist

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Abstract

Background and Objective

Daridorexant is a dual orexin receptor antagonist in clinical development for insomnia. As daridorexant is cleared mainly via cytochrome P450 (CYP) 3A4, the effect of hepatic impairment on the pharmacokinetics (PK), metabolism, and tolerability of daridorexant was evaluated. Sleep disorders are common in patients with liver cirrhosis and, therefore, sleep-promoting drugs with a better tolerability than currently available would be preferable, a premise that dual orexin receptor antagonists may fulfill.

Methods

This was a single-dose, open-label, phase I study. Subjects with mild (Child–Pugh A, N = 8) or moderate (Child–Pugh B, N = 8) liver cirrhosis and matched healthy control subjects (N = 8) received 25 mg of daridorexant orally. Blood samples were collected for 72 h post-dose for PK assessments of daridorexant and three major metabolites.

Results

Compared with healthy subjects, patients showed a decrease in total daridorexant area under the plasma concentration–time curve from zero to infinity (AUC0-inf) and maximum plasma concentration with a geometric mean ratio (GMR, 90% confidence interval [CI]) of 0.51 (0.28–0.92) and 0.50 (0.35–0.72) in Child–Pugh A and 0.74 (0.39–1.41) and 0.42 (0.29–0.60) in Child–Pugh B patients, respectively. Furthermore, the median time to reach maximum plasma concentration was slightly delayed (1.0 h [90% CI 0.0–2.0] in Child–Pugh A patients and 0.5 h [90% CI 0.0–1.5] in Child–Pugh B patients), while for Child–Pugh B patients, a doubling in half-life was observed (GMR [90% CI]: 2.09 [1.32–3.30]). Considering the high plasma protein binding (> 99%) and a 1.9-fold to 2.3-fold increase in the unbound fraction in patients, the PK of unbound daridorexant was also assessed. Compared with healthy subjects, Child–Pugh B patients had a higher AUC0-inf (GMR [90% CI] 1.60 [0.93–2.73]), a lower apparent plasma clearance (GMR [90% CI] 0.63 [0.37–1.07]), and the same doubling in the half-life observed for total daridorexant, whereas maximum plasma concentration and apparent volume of distribution were not different. Unbound daridorexant PK in Child–Pugh A patients did not differ from healthy subjects. In addition, the metabolic ratios (parent to metabolite), i.e., a marker of CYP 3A4 activity, of the two most abundant daridorexant metabolites were higher in patients with liver cirrhosis compared with healthy subjects. All treatment-emergent adverse events were transient and of mild or moderate intensity and no other treatment-related effects were apparent.

Conclusions

No safety issue of concern was detected following administration of 25 mg of daridorexant in the study population. Moderate liver cirrhosis causes impaired hepatic clearance of unbound daridorexant, which prolongs the half-life. A 25-mg dose of daridorexant should, therefore, not be exceeded in Child–Pugh B patients. A dose adjustment is not required in Child–Pugh A patients, while avoidance of daridorexant in patients with Child–Pugh C cirrhosis is recommended.

Clinical Trial Registration

ClinicalTrials.gov ID: NCT03713242.

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Fig. 1

Adapted from Muehlan et al. [17]

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Acknowledgements

The authors thank the study team of the University Hospital Basel, Basel, Switzerland (Division of Clinical Pharmacology and Toxicology) with special thanks to the study nurses Claudia Bläsi and Joyce Jesus de Santos and to Beatrice Vetter for their valuable help during the preparation and conduct of the study and the study physicians Dr. Tanja Grandinetti, Dr. Florian Pfefferkorn, and Dr. Tim Bühler, Radka Štěpánová (Aixial s.r.o., Brno, Czech Republic) for statistical analysis of the clinical data, and Susanne Globig (Department of Preclinical Pharmacokinetics and Metabolism, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland) and Mark Enzler (Swiss BioQuant AG, Reinach, Switzerland) for the bioanalytical conduct. Last but not least, the authors thank the clinical research team, i.e., Alexandre Mathis, István Kerekes, Roberta Renai, Vincent Lemoine, Priska Kaufmann, and Pascale Gasser (Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland).

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Authors and Affiliations

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

    Benjamin Berger, Jasper Dingemanse & Clemens Muehlan

  2. Department of Preclinical Drug Metabolism and Pharmacokinetics, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil, 4123, Switzerland

    Giancarlo Sabattini & Stéphane Delahaye

  3. Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, 4031, Switzerland

    Urs Duthaler & Stephan Krähenbühl

  4. Department of Biomedicine, University of Basel, Basel, 4031, Switzerland

    Urs Duthaler

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  1. Benjamin Berger
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Correspondence to Benjamin Berger.

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Funding

The study was sponsored by Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.

Conflicts of Interest

Benjamin Berger, Jasper Dingemanse, Giancarlo Sabattini, Stéphane Delahaye, and Clemens Muehlan were full-time employees of Idorsia Pharmaceuticals Ltd during the conduct of the study. Jasper Dingemanse, Stéphane Delahaye, and Clemens Muehlan own stocks (options) of Idorsia Pharmaceuticals Ltd. Urs Duthaler and Stephan Krähenbühl were employees of the University Hospital Basel (Division of Clinical Pharmacology and Toxicology) and, in addition, Urs Duthaler was also employed by the University of Basel (Department of Biomedicine) during the conduct of the study. There are no other relationships or activities that could appear to have influenced the submitted work. The University Hospital Basel (Division of Clinical Pharmacology and Toxicology) received financial compensation for the clinical conduct.

Ethics approval

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.

Consent to participate

Informed consent was obtained from all individual participants included in the study prior to any study-mandated procedure.

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Not available.

Availability of data and material

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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Not applicable.

Author contributions

JD and CM designed the study. UD and SK performed the assessments and collected the data. Data were analyzed by BB, JD, GS, SD, UD, CM, and SK. BB, JD, and SK wrote the manuscript. All authors reviewed and approved the final manuscript. The authors confirm that the principal investigator for this paper is SK and that he had direct clinical responsibility for the subjects.

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Berger, B., Dingemanse, J., Sabattini, G. et al. Effect of Liver Cirrhosis on the Pharmacokinetics, Metabolism, and Tolerability of Daridorexant, A Novel Dual Orexin Receptor Antagonist. Clin Pharmacokinet 60, 1349–1360 (2021). https://doi.org/10.1007/s40262-021-01028-8

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