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.