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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 and Physiology. 47:1843-1849
- Publication Year :
- 2020
- Publisher :
- Wiley, 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 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.
- Subjects :
- Adult
0301 basic medicine
Pyrrolidines
Physiology
Cmax
Pharmacology
Young Adult
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
Physiology (medical)
medicine
Humans
Distribution (pharmacology)
Drug Interactions
Rosuvastatin
Rosuvastatin Calcium
IC50
Chemistry
Imidazoles
Antagonist
nutritional and metabolic diseases
Middle Aged
Orexin receptor
030104 developmental biology
Tolerability
030220 oncology & carcinogenesis
medicine.drug
Subjects
Details
- ISSN :
- 14401681 and 03051870
- Volume :
- 47
- Database :
- OpenAIRE
- Journal :
- Clinical and Experimental Pharmacology and Physiology
- Accession number :
- edsair.doi.dedup.....63d8165bab096fb86eba0bf6e9b7a33c