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

• Published in: Clinical drug investigation Vol. 43; no. 11; pp. 827 - 837
• Main Authors: Anliker-Ort, Marion, Dingemanse, Jasper, Janů, Luboš, Kaufmann, Priska
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2023; Springer Nature B.V
• Subjects: Anticoagulants; Bioavailability; Blood; Breast cancer; Cancer therapies; Drug dosages; FDA approval; Glycoproteins; Insomnia; Internal Medicine; Medicine; Medicine & Public Health; Metabolism; Onsite; Original Research Article; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Proteins; Regulatory approval; Stroke; Czech Republic
• ISSN: 1173-2563; 1179-1918; 1179-1918
• DOI: 10.1007/s40261-023-01310-6

Background and Objective The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively. Methods This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7–14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2. Results Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration–time curve were 1.3 (1.0–1.7) and 1.4 (1.1–1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated. Conclusions A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected. Clinical Trial Registration NCT05480475; date of registration: 29 July, 2022.