Chemical formula: C₂₃H₂₃ClN₆O₂ Molecular mass: 450.93 g/mol
Daridorexant is a dual orexin receptor antagonist, acting on both orexin 1 and orexin 2 receptors and equipotent on both. The orexin neuropeptides (orexin A and orexin B) act on orexin receptors to promote wakefulness. Daridorexant antagonises the activation of orexin receptors by the orexin neuropeptides and consequently decreases the wake drive, allowing sleep to occur, without altering the proportion of sleep stages (as assessed by electroencephalographic recording in rodents or polysomnography in patients with insomnia).
Daridorexant is rapidly absorbed following oral administration and reaches peak plasma concentrations within 1–2 h. At an oral dose of 100 mg, daridorexant has an absolute bioavailability of 62%.
Daridorexant plasma exposure is dose proportional between 25 and 50 mg.
In healthy subjects, food did not affect total exposure. The tmax of 50 mg daridorexant was delayed by 1.3 h and Cmax decreased by 16% following administration of a high-fat and high-calorie meal.
Daridorexant has a volume of distribution of 31 L. Daridorexant is extensively bound (99.7%) to plasma proteins, mostly to albumin and to a lower extent to α-acid glycoprotein. The blood to plasma ratio is 0.64.
Daridorexant undergoes extensive metabolism and is primarily metabolised by CYP3A4 (89%). Other CYP enzymes are not of clinical relevance and individually contribute to less than 3% of metabolic clearance. None of the major human metabolites (M1, M3, and M10) contribute to the pharmacological effect of the medicinal product.
Daridorexant inhibits several CYP enzymes in vitro. The strongest inhibition was seen on CYP3A4 with a Ki of 4.6–4.8 µM. Inhibition of CYP2C8, CYP2C9, and CYP2C19 was less pronounced, with IC50 values in the range of 8.2–19 µM. Daridorexant induces CYP3A4 mRNA expression in human hepatocytes with an EC50 of 2.3 µM and, to a lesser extent, CYP2C9 and CYP2B6. Up-regulation of all CYP enzymes is mediated via activation of the PXR receptor with an EC50 of 3 µM. Daridorexant does not induce CYP1A2.
Daridorexant inhibits various transporters in vitro and had the strongest inhibitory effect on BCRP with an IC50 of 3.0 µM. Inhibition of other transporters including OATP, OAT3, OCT1, MATE-2K, MATE1, and P-gp/MDR1 was less pronounced, with IC50 values ranging from 8.4–71 µM.
The primary route of excretion is via faeces (approximately 57%), followed by urine (approximately 28%). Only traces of parent compound were found in urine and faeces.
The terminal half-life of daridorexant is approximately 8 hours.
The PK profile of daridorexant following multiple-dose administration showed similar PK parameters to those observed after single-dose administration. No accumulation was observed.
No clinically significant differences in the PK of daridorexant were detected based on age, sex, race, or body size. Limited PK data are available in patients older than 75 years.
Following administration of a single dose of 25 mg daridorexant, subjects with mild hepatic impairment (Child-Pugh score 5–6) had a similar exposure to unbound daridorexant compared to healthy subjects. In subjects with moderate hepatic impairment (Child-Pugh score 7–9), exposure to unbound daridorexant (AUC) and half-life increased by 1.6 times and 2.1 times, respectively, compared to healthy subjects.
Based on these results, a dose adjustment is recommended in patients with moderate hepatic impairment.
In patients with severe hepatic impairment (Child-Pugh score ≥ 10), daridorexant has not been studied and is not recommended.
Following administration of a single dose of 25 mg, the PK parameters of daridorexant were similar in subjects with severe renal impairment compared to healthy subjects.
Based on these results, daridorexant can be administered to patients with any degree of renal function impairment without the need for dose adjustment.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Daridorexant also showed no signs indicative of abuse potential or physical dependence.
No adverse effects were observed in repeat-dose toxicity studies in rats and dogs at exposures that are 72 times and 14 times, respectively, the human exposure at the maximum recommended dose of 50 mg/day.
In dogs under positive stimulation at play, episodes of sudden muscle weakness, reminiscent of cataplexy, were observed as exaggerated pharmacological effects of daridorexant from Week 7 onwards and did not occur after treatment cessation. An overall no-observed-effect level was established at exposures that are 45 times (females) and 78 times (males) the human exposure at 50 mg/day for the free fraction.
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