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The dual orexin receptor antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin.
- Source :
-
Clinical and experimental pharmacology & physiology [Clin Exp Pharmacol Physiol] 2020 Nov; Vol. 47 (11), pp. 1843-1849. Date of Electronic Publication: 2020 Jul 21. - Publication Year :
- 2020
-
Abstract
- 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 IC <subscript>50</subscript> 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 C <subscript>max</subscript> and AUC <subscript>0-∞</subscript> . 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.<br /> (© 2020 John Wiley & Sons Australia, Ltd.)
- Subjects :
- Humans
Male
Adult
Young Adult
Middle Aged
Pyrimidines pharmacokinetics
Pyrimidines administration & dosage
Pyrimidines pharmacology
Imidazoles
Pyrrolidines
Rosuvastatin Calcium pharmacokinetics
Rosuvastatin Calcium administration & dosage
ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism
Orexin Receptor Antagonists pharmacokinetics
Orexin Receptor Antagonists pharmacology
Orexin Receptor Antagonists administration & dosage
Neoplasm Proteins antagonists & inhibitors
Neoplasm Proteins metabolism
Drug Interactions
Subjects
Details
- Language :
- English
- ISSN :
- 1440-1681
- Volume :
- 47
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Clinical and experimental pharmacology & physiology
- Publication Type :
- Academic Journal
- Accession number :
- 32603512
- Full Text :
- https://doi.org/10.1111/1440-1681.13370