Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia.
of daridorexant include headache, somnolence, and fatigue.
Daridorexant was approved for medical use in the United States in January 2022[ ] Besides daridorexant, other orexin receptor antagonists, like suvorexant and lemborexant, have also been introduced.
Medical uses
Daridorexant is
indicated for the treatment of adults with
insomnia characterized by difficulties with
sleep onset and/or sleep maintenance.
The medication has been found to significantly improve latency to persistent sleep (LPS), wake after sleep onset (WASO), and subjective total sleep time (TST) in regulatory clinical trials.
At doses of 25 to 50mg and in terms of treatment–
placebo difference, it reduces LPS by 6 to 12minutes, reduces WASO by 10 to 23minutes, and increases subjective TST by 10 to 22minutes.
Daridorexant has also been found to improve daytime functioning at a dose of 50mg but not at 25mg.
Network meta-analyses have assessed the sleep-promoting effects of orexin receptor antagonists and have compared them between one another as well as to other sleep aids including , , , sedative (e.g., trazodone, doxepin, amitriptyline, mirtazapine), and melatonin receptor agonists.
Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability.
Population Pharmacokinetics modeling indicates that differences between subjects do not require dose adjustments, and that lean body weight and fat mass effect the pharmacokinetics of daridorexant better than other body size descriptors.
Treatment with daridorexant is generally safe and well tolerated for up to one year, with improvements in sleep and daytime functioning persisting throughout treatment.
The Department of Defense (DOD) is testing the effectiveness of daridorexant in patients with post-traumatic stress disorder (PTSD) as the link between insomnia and PTSD is well established.
Available forms
In the United States and Canada, daridorexant is available in the form of 25 and 50mg oral tablets.
It is provided as the salt daridorexant hydrochloride, with each tablet containing 27 or 54mg of this substance (equivalent to 25 or 50mg daridorexant).
Contraindications
Daridorexant is
contraindication in people with
narcolepsy.
It is not recommended in people with severe hepatic impairment, whereas a lower maximum dose is recommended in people with moderate hepatic impairment.
Concomitant use of daridorexant with strong CYP3A4
enzyme inhibitor and moderate to strong CYP3A4
enzyme inducer is not recommended and should be avoided due to unfavorable modification of daridorexant exposure.
Side effects
of daridorexant include
headache (6% at 25mg vs. 7% at 50mg vs. 5% for
placebo),
somnolence or fatigue (includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25mg vs. 5% at 50mg vs. 4% for
placebo),
dizziness (2% at 25mg vs. 3% at 50mg vs. 2% for placebo), and
nausea (0% at 25mg vs. 3% at 50mg vs. 2% for placebo).
No residual effects have been found after administration of 25mg daridorexant in the evening to either young or elderly individuals.
However, daridorexant may cause next-morning driving impairment at the start of treatment or in some individuals.
Orexin receptor antagonists like daridorexant may have less or no propensity for causing
drug tolerance compared to other sedatives and hypnotics based on animal studies.
Daridorexant did not produce signs of
drug withdrawal or
drug dependence upon discontinuation in animal studies and clinical trials, and orexin receptor antagonists are not associated with
rebound insomnia.
Loss of sleep-promoting effectiveness occurs rapidly upon discontinuation of daridorexant.
Preclinical research has suggested that orexin antagonists may reduce
appetite, but daridorexant and other orexin antagonists have not been associated with
weight loss in
.
Daridorexant may have a small risk of suicidal ideation.
Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans.
Overdose
There is limited clinical experience with
overdose of daridorexant.
Overdose of the medication at a dose of up to four times the maximum recommended dose may result in
including
somnolence,
muscle weakness,
cataplexy-like symptoms,
sleep paralysis,
attention disturbances, fatigue,
headache, and
constipation.
There is no specific
antidote to overdose of daridorexant.
Interactions
CYP3A4
enzyme inhibitor and
enzyme inducer can increase and decrease exposure to daridorexant, respectively.
The weak CYP3A4 inhibitor
ranitidine (150mg) is predicted to increase overall exposure to daridorexant by 1.5-fold; the moderate CYP3A4 inhibitor
diltiazem (240mg) increased exposure to daridorexant by 2.4-fold; and the strong CYP3A4 inhibitor
itraconazole, on the basis of physiologically-based pharmacokinetic modeling, would be expected to increase daridorexant exposure by more than 4-fold.
Conversely, the moderate CYP3A4 inducer
efavirenz (600mg) decreased daridorexant overall exposure by 35 to 60% and the strong CYP3A4 inducer
rifampin similarly decreased daridorexant exposure by more than 50%.
Concomitant use of daridorexant with strong CYP3A4 inhibitors or with moderate or strong CYP3A4 inducers should be avoided, while it is recommended that the maximum dose of daridorexant be reduced with moderate CYP3A4 inhibitors.
Examples of important CYP3A4 modulators which are expected to interact with daridorexant include the strong CYP3A4 inhibitors boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, and telithromycin (concomitant use not recommended); the moderate CYP3A4 inhibitors amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, grapefruit juice, imatinib, and verapamil (lower doses of daridorexant recommended); and the strong CYP3A4 inducers apalutamide, carbamazepine, efavirenz, enzalutamide, phenytoin, rifampin, and St. John's wort (expected to decrease daridorexant effectiveness).
Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure.
Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (a CYP3A4 substrate), rosuvastatin (a BCRP substrate), and the SSRI citalopram (primarily a CYP2C19 substrate).
Pharmacology
Pharmacodynamics
Daridorexant acts as a selective dual antagonist of the
orexin receptor OX
1 and OX
2.
The affinities (K
i) of daridorexant for the orexin receptors are 0.47nM for the OX
1 receptor and 0.93nM for the OX
2 receptor.
Its K
b values for the human orexin receptors have been reported to be 0.5nM for the OX
1 receptor and 0.8nM for the OX
2 receptor.
Hence, daridorexant is approximately
equipotent in its antagonism of the orexin receptors.
Daridorexant is selective for the orexin receptors over many other targets.
In contrast to certain other sedatives and hypnotics, daridorexant is not a
benzodiazepine or
Z-drug and does not interact with
.
Mechanism of action
The
endogenous orexin ,
orexin A and
orexin B, are involved in the regulation of sleep–wake cycles and act to promote
wakefulness.
Deficiency of orexin signaling is thought to be the primary cause of the
sleep disorder narcolepsy.
Disturbances in orexin signaling may also be involved in
insomnia.
Research suggests that orexin signaling may change with age, and this has been implicated in
aging-related sleep disturbances.
By blocking the actions of orexins and modulating sleep–wake cycles, orexin receptor antagonists like daridorexant reduce wakefulness and improve sleep.
The sleep-promoting effects of dual orexin receptor antagonists are thought to be mediated specifically by blockade of the OX
2 receptor in the lateral hypothalamus.
Although narcoleptic symptoms were a theoretical concern during the development of orexin receptor antagonists, this has not been observed in clinical trials of these agents.
Pharmacokinetics
Absorption
The absolute bioavailability of daridorexant is 62%.
The poor aqueous solubility of daridorexant limits its
bioavailability.
It reaches peak concentrations within 1 to 2hours following a dose.
Food prolonged the time to peak by 1.3 to 2hours and decreased the peak concentrations by 16 to 24%, but did not affect area-under-the-curve concentrations.
Distribution
The volume of distribution of daridorexant is 31L.
Its plasma protein binding is 99.7%.
The plasma-to-blood ratio of daridorexant is 0.64.
Daridorexant is a
lipophilic molecule and effectively crosses the blood–brain barrier in animals.
Metabolism
Daridorexant is extensively
metabolism primarily by CYP3A4 (89%).
Other cytochrome P450
contribute individually to less than 3% of the clearance of daridorexant.
Daridorexant has 77 identified
.
Its major metabolites are less active than daridorexant as orexin receptor antagonists.
Recently, a study was carried out using human liver reported that daridorexant underwent 3 reaction; hydroxylation at the methyl group of the benzimidazole moiety, oxidative O-demethylation of the anisole to the corresponding Phenols, and hydroxylation to a 4-hydroxy piperidinol derivative. Researchers proved that the chemical structures of the benzylic alcohol and the Phenols are products of standard CYP450 reactions; while the latter hydroxylation product was incompatible with the initially postulated hydroxylation of the pyrrolidine ring, hence they suggested that human monooxygenase CYP3A4 catalyzes the intramolecular rearrangement of daridorexant. In detail, they proposed the following mechanism, hydroxylation in 5-position of the pyrrolidine ring initially will yield a cyclic hemiaminal which subsequently will Hydrolysis to a ring-open Amine aldehyde. Afterwards, cyclization of the latter onto one of the nitrogen atoms of the benzimidazole moiety will yield the final 4-hydroxy piperidinol metabolite.
Elimination
Daridorexant is eliminated primarily by
feces (57%) then by
urine (28%).
It is
excretion mainly in the form of
, with only trace amounts of the parent compound identified.
The medication has an elimination half-life of about 8hours
Chemistry
Daridorexant is a
small-molecule compound.
The
chemical name of daridorexant is (
S)-(2-(5-chloro-4-methyl-1
H-benzodimidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2
H-1,2,3-triazol-2-yl)phenyl)methanone.
Its molecular formula is C
23H
23N
6O
2Cl and its
molecular weight is 450.93g/mol (or 487.38g/mol for the hydrochloride).
Daridorexant hydrochloride is a white to light yellowish powder.
Daridorexant is a
lipophilic compound and daridorexant hydrochloride is very slightly
water solubility in water.
History
Daridorexant was originated by Actelion Pharmaceuticals and was further developed by
Idorsia.
[ Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] It was
in 2013
and was first described in the scientific literature in 2017.
It was in development for 25 years by the husband-wife team Jean-Paul and
Martine Clozel.
Daridorexant was approved for medical use in the United States in January 2022
and became available in May 2022.
On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Quviviq, intended for the treatment of insomnia.
Society and culture
Legal status
Daridorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States.
Daridorexant (Quviviq) was approved for medical use in the European Union in April 2022.[ Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.]
Daridorexant (Quviviq) was approved by Health Canada in April 2023.
Further reading
-
(review of 7 randomized studies with 2.425 participants; selected by the Sardinia's Pharmacovigilance)
