Daridorexant is a dual orexin receptor antagonist in clinical development for the treatment of insomnia. Breast-cancer resistant protein (BCRP) is an efflux pump expressed in intestinal epithelium and hepatocytes, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds. In vitro, daridorexant inhibits BCRP with an IC50 of 3.0 μmol/L. The BCRP substrate rosuvastatin is a cholesterol-lowering drug, recommended for clinical drug-drug interaction (DDI) studies. In order to exclude an inhibitory effect of daridorexant on BCRP, this single-centre, open-label, two-treatment Phase 1 study investigated the effect of daridorexant at steady state on the pharmacokinetics (PK) of single-dose rosuvastatin in 20 healthy male subjects. In addition, safety and tolerability were assessed. A single oral dose of 10 mg rosuvastatin on Day 1 was followed by 96 hours observation. Thereafter, 25 mg daridorexant was administered once daily (o.d.) on Days 5-8 and in combination with 10 mg rosuvastatin on Day 8. On Days 9-12, subjects received 25 mg daridorexant alone. PK sampling was performed up to 120 hours after treatment administration. The results showed that concomitant administration of 25 mg daridorexant o.d. at steady state did not affect the exposure parameters of rosuvastatin in a relevant way, as indicated by the ratios of geometric means (GMRs) ([rosuvastatin + daridorexant]/[rosuvastatin alone]) of 0.93 for both Cmax and AUC0-∞ . Administration of a single dose of 10 mg rosuvastatin, multiple doses of 25 mg daridorexant alone or in combination were well tolerated. Taken together, daridorexant and BCRP substrates can be safely co-administered.

CEPHA s r o Komenskeho 19 Pilsen Czech Republic

Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd Allschwil Switzerland

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Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:573-585.

Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8:171-181.

Muehlan C, Heuberger J, Juif PE, et al. Accelerated development of the dual orexin receptor antagonist ACT-541468: integration of a microtracer in a first-in-human study. Clin Pharmacol Ther. 2018;104:1022-1029.

Dauvilliers Y, Zammit G, Fietze I, et al. Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder. Ann Neurol. 2020;87:347-356.

Treiber A, De Kanter R, Roch C, et al. The use of physiology-based pharmacokinetic and pharmacodynamic modeling in the discovery of the dual orexin receptor antagonist ACT-541468. J Pharmacol Exp Ther. 2017;362:489-503.

Muehlan C, Brooks S, Zuiker R, et al. Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration. Eur Neuropsychopharmacol. 2019;29:847-857.

Boof ML, Alatrach A, Ufer M, et al. Interaction potential of the dual orexin receptor antagonist ACT-541468 with CYP3A4 and food: results from two interaction studies. Eur J Clin Pharmacol. 2019;75:195-205.

Muehlan C, Zuiker R, Peeters P, et al. Pharmacokinetics and pharmacodynamics of the dual orexin receptor antagonist daridorexant in Japanese and caucasian subjects. J Clin Psychopharmacol. 2020;40:157-166.

Zammit G, Dauvilliers Y, Pain S, et al. Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with insomnia disorder. Neurology. 2020;94(21):e2222-e2232.

Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport-an update. AAPS J. 2015;17:65-82.

Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry | FDA, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. Accessed February 24, 2020).

Crestor 10 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc), https://www.medicines.org.uk/emc/product/7559/smpc. Accessed February 6, 2020.

Martin PD, Warwick MJ, Dane AL, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther. 2003;25:2822-2835.

Cooper KJ, Martin PD, Dane AL, et al. The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol. 2002;58:527-531.

Pan Y, Hsu V, Grimstein M, et al. The application of physiologically based pharmacokinetic modeling to predict the role of drug transporters: scientific and regulatory perspectives. J Clin Pharmacol. 2016;S122-S131.

Giacomini KM, Huang SM, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discovery. 2010;9:215-236.

Özdemir V, Kalow W, Tang BK, et al. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics. 2000;10:373-388.

Sturzenegger C, Baumann CR, Lammers GJ, et al. Swiss narcolepsy scale. Clin Transl Neurosci. 2018;2:1-5.

Martin P, Gillen M, Ritter J, et al. Effects of fostamatinib on the pharmacokinetics of oral contraceptive, warfarin, and the statins rosuvastatin and simvastatin: results from phase I clinical studies. Drugs R D. 2016;16:93-107.

Effect of Daridorexant on the Pharmacokinetics of P-Glycoprotein Substrate Dabigatran Etexilate and Breast Cancer Resistance Protein Substrate Rosuvastatin in Healthy Subjects