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

Abstract

AimsDaridorexant 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.MethodsIn 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.ResultsWhen daridorexant administration was preceded by administration of famotidine, daridorexant Cmax decreased by 39%, geometric means ratio (GMR) (90% confidence interval [90% CI]): 0.61 (0.50, 0.73). AUC0‐∞ remained unchanged. In the presence of steady‐state efavirenz, daridorexant Cmax, AUC0‐∞ and t½ 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. tmax remained unaffected. All treatments containing daridorexant were well tolerated.ConclusionDaridorexant 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.

Daridorexant: First Approval

“…Daridorexant at a dose of 50 mg can be coadministered with the histamine 2 receptor inhibitor famotidine without dosage adjustment [19]. Coadministration of daridorexant 50 mg with the SSRI citalopram was not associated with clinically relevant changes in pharmacokinetic parameters [20].…”

“…Coadministration of daridorexant 25 mg with the moderate CYP3A4 inhibitor diltiazem increased daridorexant AUC by 240%, and, based on physiologically-based pharmacokinetic modelling, coadministration with the strong CYP3A4 inhibitor itraconazole is expected to increase daridorexant AUC by > 400% [22]. Conversely, coadministration of daridorexant with the moderate CYP3A4 inducer efavirenz decreased daridorexant AUC by ≈ 35% [19] and coadministration with the strong CYP3A4 inducer rifampin is expected to decrease daridorexant AUC by > 50% [22]. On this basis, the maximum recommended dose of daridorexant is 25 mg when used concomitantly with a moderate CYP3A4 inhibitor, and concomitant use of daridorexant and a strong CYP3A4 inhibitor, or moderate or strong CYP3A4 inducer is not recommended [5].…”

Daridorexant for the Treatment of Insomnia

“…58 It is highly bound to plasma proteins (99.7%), its volume of distribution (Vd) is 31 L, and the total area under the curve (AUC) is not hindered by a high-fat meal but does reduce its C max by 16% and increases the t max by 1.3 h. 58 In pharmacokinetic modelling studies, AUC for daridorexant escalated by 240% and > 400% when used concomitantly with moderate CYP3A4 inhibitor diltiazem and strong CYP3A4 inhibitor itraconazole, respectively; whereas AUC decreased by ~ 30% and > 50% when used with moderate CYP3A4 inducer efavirenz and strong CYP3A4 inducer rifampin, respectively. 59,90 There were no interactions or changes in the pharmacokinetic profile of daridorexant 50 mg when used with famotidine, citalopram, or rosuvastatin. [90][91][92] However, concomitant administration of ethanol and daridorexant hindered psychomotor functioning and prolonged the t max .…”

“…59,90 There were no interactions or changes in the pharmacokinetic profile of daridorexant 50 mg when used with famotidine, citalopram, or rosuvastatin. [90][91][92] However, concomitant administration of ethanol and daridorexant hindered psychomotor functioning and prolonged the t max . 59,93 Moreover, studies found a reduction in attention and vigilance, postural instability, and impaired visual-motor coordination when used in advancing doses and used with other CNS depressants.…”

Daridorexant: A New Dual Orexin Receptor Antagonist for Insomnia

“…5,23 Daridorexant 50 mg does not require a dose adjustment when taken concomitantly with gastric pH modifiers or moderate CYP3A4 inducers. 24 Daridorexant is also a central nervous system (CNS) depressant and may cause additive effects with other CNS depressants such as tricyclic antidepressants, benzodiazepines, or alcohol. Caution should be used when prescribing daridorexant with concomitant CNS depressants and a dose adjustment should be considered.…”