Effect of gastric pH and of a moderate CYP3A4 inducer on the pharmacokinetics of daridorexant, a dual orexin receptor antagonist

Aims Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The solubility of daridorexant is pH-dependent and daridorexant has been shown to be a sensitive CYP3A4 substrate when co-administered with moderate CYP3A4 inhibitors. The purpose of this study was to assess the effect of an increased gastric pH on daridorexant pharmacokinetics (PK) and the extent of interaction when daridorexant is co-administered with a moderate CYP3A4 inducer. Methods In this prospective, single-centre, randomized, open-label study, 24 male subjects consecutively received four treatments, i.e., daridorexant 50 mg single dose; famotidine 40 mg single dose + daridorexant 50 mg single dose; efavirenz 600 mg once a day (o.d.) for 10 days; and daridorexant 50 mg single dose + efavirenz 600 mg o.d. for 2 days. Plasma PK parameters of daridorexant were derived by noncompartmental analysis. Standard safety and tolerability evaluations were analysed descriptively. Results When daridorexant administration was preceded by administration of famotidine, daridorexant C-max decreased by 39%, geometric means ratio (GMR) (90% confidence interval [90% CI]): 0.61 (0.50, 0.73). AUC(0-infinity) remained unchanged. In the presence of steady-state efavirenz, daridorexant C-max, AUC(0-infinity) and t(1/2) decreased by approximately 35% (GMR [90% CI]): 0.65 (0.54, 0.78), 61% (0.39 (0.348, 0.44), and 35% (0.65 (0.58, 0.73), respectively. t(max) remained unaffected. All treatments containing daridorexant were well tolerated. Conclusion Daridorexant 50 mg can be administered concomitantly with gastric pH modifiers or with moderate CYP3A4 inducers without dose adaptation based on efficacy observed at lower doses in Phase 3 studies.