Search

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-∞ remained unchanged. In the presence of steady-state efavirenz, daridorexant C max , AUC 0-∞ and t ½ 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., (© 2021 British Pharmacological Society.)

Aim: The aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg -1 twice daily (b.i.d.) to 2 mg kg -1 three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from ≥3 months to <12 years of age) would increase exposure., Methods: An open-label, prospective, randomized, multicentre, multiple-dose, phase III study was conducted. Patients (n = 64) were randomized 1:1 to receive oral doses of bosentan of 2 mg kg -1 b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to bosentan over 24 h corrected to the 2 mg kg -1 dose (AUC 0-24C ). The maximum plasma concentration corrected to the 2 mg kg -1 dose (C maxC ), the time to reach the maximum plasma concentration (t max ) and safety endpoints were also assessed., Results: The geometric mean [95% confidence interval (CI)] for AUC 0-24C was 8535 h.ng ml -1 (6936, 10 504) and 7275 h.ng ml -1 (5468, 9679) for 2 mg kg -1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for C maxC was 743 ng ml -1 (573, 963) and 528 ng ml -1 (386, 722) for 2 mg kg -1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for t max was 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg kg -1 b.i.d. and t.i.d., respectively. The proportions of patients who experienced ≥1 adverse event were similar in the b.i.d. (66.7%) and t.i.d. (67.7%) groups., Conclusions: There appeared to be no clinically relevant difference in exposure to bosentan, or in safety, when increasing the frequency of bosentan dosing from b.i.d. to t.i.d. Therefore, the present study provides no indication that the dosing recommendation should be changed, and 2 mg kg -1 b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients., (© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)