Daridorexant, sold under the brand name Quviviq, is an
orexin antagonist An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders su ...
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
which is used for the treatment of
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
.
Daridorexant is taken
by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
.
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s of daridorexant include
headache,
somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
, and
fatigue.
The medication is a
dual orexin receptor antagonist (DORA).
It acts as a
selective dual
antagonist of the
orexin receptor
The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (, ).
Both orexin receptors exhibit ...
s
OX1 and
OX2.
Daridorexant has a relatively short
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
of 8hours and a
time to peak of about 1 to 2hours.
It is not a
benzodiazepine or
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...
and does not interact with
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...
s, instead having a distinct
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...
.
Daridorexant was approved for medical use in the United States in January 2022
and became available in May 2022.
It was approved in the European Union in April 2022, and is the first orexin receptor antagonist to become available in European Union.
The medication is a
schedule IV controlled substance
A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single ...
in the United States and may have a modest
potential for misuse
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
.
[ ] Besides daridorexant, other orexin receptor antagonists, like
suvorexant and
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
, have also been introduced.
Medical uses
Daridorexant is
indicated
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for the treatment of adults with
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
characterized by difficulties with
sleep onset
Sleep onset is the transition from wakefulness into sleep. Sleep onset usually transmits into non-rapid eye movement sleep (NREM sleep) but under certain circumstances (e.g. narcolepsy) it is possible to transit from wakefulness directly into rapid ...
and/or
sleep maintenance.
The medication has been found to significantly improve
latency to persistent sleep
In sleep science, sleep onset latency (SOL) is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages.
Sleep latency studies
Pioneering Stanford Universi ...
(LPS),
wake after sleep onset
Middle-of-the-night insomnia (MOTN) is characterized by having difficulty returning to sleep after waking up during the night or very early in the morning. This kind of insomnia (sleeplessness) is different from initial or sleep-onset insomnia, whi ...
(WASO), and subjective
total sleep time
Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a de ...
(TST) in regulatory clinical trials.
At doses of 25 to 50mg and in terms of treatment–
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
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.
It is the first insomnia medication to have been evaluated and shown effectiveness in improving not only nighttime symptoms but also daytime functioning.
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
benzodiazepines,
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...
s,
antihistamine
Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provid ...
s, sedative
antidepressants (e.g.,
trazodone
Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and difficulties with sleep. The medication is taken orally.
Common side-effects include dry mouth, f ...
,
doxepin
Doxepin is a medication falling in the tricyclic antidepressant (TCA) class used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For label updates seFDA index page for NDA 022036/ref> For hives it is a less ...
,
amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...
,
mirtazapine
Mirtazapine, sold under the brand name Remeron amongst others, is an Atypical antidepressant, atypical antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks, but can also man ...
), and
melatonin receptor agonist
Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The disc ...
s.
A major
systematic review and network meta-analysis of insomnia medications published in 2022 found that daridorexant had an
effect size
In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...
(
standardized mean difference (SMD)) against
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
for treatment of insomnia at 4weeks of 0.23 (95% –0.01 to 0.48).
This was similar to but numerically lower than the effect sizes at 4weeks for
suvorexant (SMD 0.31, 95% CI 0.01 to 0.62) and
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
(SMD 0.36, 95% CI 0.08 to 0.63).
Benzodiazepines and Z-drugs generally showed larger effect sizes than orexin receptor antagonists (e.g., SMDs of 0.45 to 0.83).
The review concluded on the basis of daridorexant's small effect size that it did not show an overall material benefit in the treatment of insomnia.
Conversely, it concluded that lemborexant—as well as the Z-drug
eszopiclone
Eszopiclone, sold under the brand-name Lunesta among others such as Night Calm in Egypt, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken orally.
Common side effects i ...
—had the best profiles overall in terms of
efficacy,
tolerability
Tolerability refers to the degree to which overt adverse effects of a drug can be tolerated by a patient. Tolerability of a particular drug can be discussed in a general sense, or it can be a quantifiable measurement as part of a clinical study. U ...
, and
acceptability
Acceptability is the characteristic of a thing being subject to acceptance for some purpose. A thing is acceptable if it is sufficient to serve the purpose for which it is provided, even if it is far less usable for this purpose than the ideal exa ...
among all of the assessed insomnia medications.
Orexin receptor antagonists are not used as
first-line treatment
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
s for insomnia due to their costs and concerns about possible
misuse liability.
Available forms
Daridorexant is available in the form of 25 and 50mg
oral
The word oral may refer to:
Relating to the mouth
* Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid
**Oral administration of medicines
** Oral examination (also known as an oral exam or or ...
tablets.
It is provided as the
salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...
daridorexant hydrochloride, with each tablet containing 27 or 54mg of this substance (equivalent to 25 or 50mg daridorexant).
Contraindications
Daridorexant is
contraindicated
In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
in people with
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...
.
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 inhibitors and moderate to strong CYP3A4
inducer
In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely:
*By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...
s is not recommended and should be avoided due to unfavorable modification of daridorexant exposure.
Side effects
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s of daridorexant include
headache (6% at 25mg vs. 7% at 50mg vs. 5% for
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
),
somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
or
fatigue (includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25mg vs. 5% at 50mg vs. 4% for
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
),
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
(2% at 25mg vs. 3% at 50mg vs. 2% for placebo), and
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
(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
tolerance compared to other sedatives and hypnotics based on animal studies.
Daridorexant did not produce signs of
withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
or
dependence upon
discontinuation in animal studies and clinical trials, and orexin receptor antagonists are not associated with
rebound insomnia
The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of r ...
.
Loss of sleep-promoting effectiveness occurs rapidly upon discontinuation of daridorexant.
Preclinical research
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
has suggested that orexin antagonists may reduce
appetite, but daridorexant and other orexin antagonists have not been associated with
weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...
in rigorous
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s.
Daridorexant may have a small risk of
suicidal ideation.
Orexin receptor antagonists can affect the
reward system and produce
drug-liking responses in humans.
Daridorexant at a dose of 50mg (the maximum recommended dose) showed significantly greater drug liking than
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
but significantly less drug liking than
zolpidem
Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavior ...
(30mg) and
suvorexant (150mg) in recreational sedative drug users.
At higher doses of 100 and 150mg (greater than the recommended maximum dose), drug liking with daridorexant was similar to that with zolpidem (30mg) and suvorexant (150mg).
In other studies, suvorexant showed similar drug liking compared to zolpidem but lower misuse potential on other measures (e.g., overall rate of misuse potential adverse events of 58% for zolpidem and 31% for suvorexant in recreational drug users).
No reports indicative of
misuse liability were observed in large clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse.
Overdose
There is limited clinical experience with
overdose
A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. of daridorexant.
Overdose of the medication at a dose of up to four times the maximum recommended dose may result in
adverse effect
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...
s including
somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
,
muscle weakness,
catalepsy
Catalepsy (from Ancient Greek , , "seizing, grasping") is a nervous condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain.
Signs and symptoms
Symptoms in ...
-like symptoms,
sleep paralysis
Sleep paralysis is a state, during waking up or falling asleep, in which one is conscious but is completely paralyzed. During an episode, one may hallucinate (hear, feel, or see things that are not there), which often results in fear. Episod ...
,
attention disturbances,
fatigue,
headache, and
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
.
There is no specific
antidote
An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...
to overdose of daridorexant.
Interactions
CYP3A4 inhibitors and
inducer
In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely:
*By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...
s can increase and decrease exposure to daridorexant, respectively.
The weak CYP3A4 inhibitor
ranitidine
Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome ...
(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
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mo ...
, 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
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used tog ...
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
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clarith ...
,
conivaptan
Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). The compound was discovered by As ...
,
indinavir
Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. ...
,
itraconazole
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mo ...
,
ketoconazole,
lopinavir
Lopinavir is an anti retroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).
It was patented in 1995 and approved for medical ...
,
nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...
,
nelfinavir
Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is almost always used in combination ...
,
posaconazole
Posaconazole, sold under the brand name Noxafil among others, is a triazole antifungal medication.
It was approved for medical use in the United States in September 2006, and is available as a generic medication.
Medical uses
Posaconazole is u ...
,
ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor ...
,
saquinavir
Saquinavir (SQV), sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect ...
,
telaprevir
Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as ...
, and
telithromycin
Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek. It is used to treat community acquired pneumonia of mild to moderate severity. After significant safety concerns, the US Food and Drug ...
(concomitant use not recommended); the moderate CYP3A4 inhibitors
amprenavir,
aprepitant,
atazanavir
Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other ...
,
ciprofloxacin
Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin inf ...
,
diltiazem,
dronedarone
Dronedarone, sold under the brand name Multaq, is a medication by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It was recommended as an alternative to amiodarone for the treatment ...
,
erythromycin,
fluconazole
Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to pr ...
,
fluvoxamine
Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...
,
fosamprenavir,
grapefruit juice
Grapefruit juice is the juice from grapefruits. It is rich in vitamin C and ranges from sweet-tart to very sour. Variations include white grapefruit, pink grapefruit and ruby red grapefruit juice.The World's Healthiest Foods; Grapefruit. ''The ...
,
imatinib, and
verapamil
Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be ...
(lower doses of daridorexant recommended); and the strong CYP3A4 inducers
apalutamide
Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatme ...
,
carbamazepine
Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...
,
efavirenz,
enzalutamide
Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrat ...
,
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
,
rifampin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used tog ...
, and
St. John's wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''.
Possibly a hybrid between ''Hypericum maculatum, H. maculatum'' and ''Hypericum attenuatum, H. ...
(expected to decrease daridorexant effectiveness).
Gastric
pH modifiers like
famotidine
Famotidine, sold under the brand name Pepcid among others, is a histamine H2 receptor antagonist medication that decreases stomach acid production. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Elli ...
can decrease
peak levels of daridorexant without affecting total exposure.
Alcohol and
selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
s (SSRIs) like
citalopram
Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and so ...
have not shown significant
pharmacokinetic interaction
Interaction is action that occurs between two or more objects, with broad use in philosophy and the sciences. It may refer to:
Science
* Interaction hypothesis, a theory of second language acquisition
* Interaction (statistics)
* Interactions o ...
s with daridorexant.
Coadministration of daridorexant with other
sedatives like
benzodiazepines,
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
s,
tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
s, and alcohol may increase the risk of
central nervous system depression
Central nervous system (CNS) depression is a physiological state that can result in a decreased rate of breathing, decreased heart rate, and loss of consciousness possibly leading to coma or death.
It is the result of inhibited or suppressed brai ...
and
daytime impairment.
Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including
midazolam
Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of ...
(a CYP3A4
substrate),
rosuvastatin
Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids. It is recommended to be used together with dietary changes, exercise, ...
(a
BCRP
ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ''ABCG2'' gene. ABCG2 has also been designated as CDw338 (cluster of differentiation w338). ABCG2 is a translocation protein used to actively pump drugs a ...
substrate), and the SSRI citalopram (primarily a
CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...
substrate).
Pharmacology
Pharmacodynamics
Daridorexant acts as a
selective dual
antagonist of the
orexin (hypocretin) receptors
OX1 and
OX2.
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 mathematics, two sets or classes ''A'' and ''B'' are equinumerous if there exists a one-to-one correspondence (or bijection) between them, that is, if there exists a function from ''A'' to ''B'' such that for every element ''y'' of ''B'', the ...
in its antagonism of the orexin receptors.
Daridorexant is
selective for the orexin receptors over many other
target
Target may refer to:
Physical items
* Shooting target, used in marksmanship training and various shooting sports
** Bullseye (target), the goal one for which one aims in many of these sports
** Aiming point, in field artillery, f ...
s.
In contrast to certain other sedatives and hypnotics, daridorexant is not a
benzodiazepine or
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...
and does not interact with
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...
s.
Mechanism of action
The
endogenous orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy) ...
neuropeptide
Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s,
orexin A and
orexin B, are involved in the regulation of
sleep–wake cycle
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
s and act to promote
wakefulness
Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognitive and behavioral responses to the external world.
Being awake is the opposite of being asleep, in which m ...
.
Deficiency of orexin signaling is thought to be the primary cause of the
sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are tests ...
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...
.
Disturbances in orexin signaling may also be involved in
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
.
Research suggests that orexin signaling may change with age, and this has been implicated in
age
Age or AGE may refer to:
Time and its effects
* Age, the amount of time someone or something has been alive or has existed
** East Asian age reckoning, an Asian system of marking age starting at 1
* Ageing or aging, the process of becoming older ...
-related
sleep disturbance
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are tests ...
s.
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
The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognit ...
.
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
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100 ...
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
In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...
of daridorexant is 31L.
Its
plasma protein binding
Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...
is 99.7%.
The
plasma-to-blood ratio of daridorexant is 0.64.
Daridorexant is a
lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
molecule and effectively crosses the
blood–brain barrier in animals.
Metabolism
Daridorexant is extensively
metabolized
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
primarily by
CYP3A4 (89%).
Other
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s contribute individually to less than 3% of the
clearance of daridorexant.
Daridorexant has 77 identified
metabolites.
Its major metabolites are less active than daridorexant as orexin receptor antagonists.
Elimination
Daridorexant is
eliminated primarily by
feces (57%) then by
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra.
Cellular ...
(28%).
It is
excreted
Excretion is a process in which metabolic waste
is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
mainly in the form of
metabolites, with only trace amounts of the parent compound identified.
The medication has an
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
of about 8hours
or of 6 to 10hours.
The half-life of daridorexant may be longer in elderly individuals compared to young adults (9–10hours in the elderly versus 6hours in young adults).
Its half-life is shorter than that of other
orexin receptor antagonist An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders s ...
s such as
suvorexant (12hours) and
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
(~18–55hours).
The relatively short half-life of daridorexant may allow for reduced daytime sedation.
The
duration of action
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ( ...
of daridorexant in terms of sedative effects is approximately 8hours with a 50mg dose.
Chemistry
Daridorexant is a
small-molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
compound.
The
chemical name of daridorexant is (''S'')-(2-(5-chloro-4-methyl-1''H''-benzo
midazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2''H''-1,2,3-triazol-2-yl)phenyl)methanone.
Its
molecular formula
In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...
is C
23H
23N
6O
2Cl and its
molecular weight
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
is 450.93g/mol (or 487.38g/mol for the hydrochloride).
Daridorexant hydrochloride is a white to light yellowish powder.
Daridorexant is a
lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
compound and daridorexant hydrochloride is very slightly
soluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubi ...
in water.
History
Daridorexant was
patent
A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...
ed in 2013
[ ] and was first described in the
scientific literature
: ''For a broader class of literature, see Academic publishing.''
Scientific literature comprises scholarly publications that report original empirical and theoretical work in the natural and social sciences. Within an academic field, scie ...
in 2017.
It 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
The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regardin ...
(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.
On 29 April 2022, daridorexant was authorized for use in the
European Union
The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been de ...
.
It was the first orexin receptor antagonist to become available for use in the European Union.
(The earlier orexin receptor antagonists
suvorexant and
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
are not available in the European Union.)
Regulatory review is also ongoing in
Canada
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...
and
Switzerland and is planned for the
United Kingdom
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...
.
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.]
Society and culture
Legal status
Daridorexant is a
schedule IV controlled substance
A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single ...
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.]
References
Further reading
*
*
External links
*
{{Portal bar , Medicine
Benzimidazoles
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Hypnotics
Orexin antagonists
Pyrrolidines
Triazoles