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Daridorexant API Manufacturers & Suppliers

General Description:

Daridorexant, identified by CAS number 1505484-82-1, is a notable compound with significant therapeutic applications. Daridorexant, formerly known as nemorexant, is a selective dual orexin receptor antagonist used to treat insomnia. Insomnia is characterized by difficulties with sleep onset and/or sleep maintenance and impairment of daytime functioning. It chronically affects the person's daily functioning and long-term health effects, as insomnia is often associated with comorbidities such as hypertension, diabetes, and depression. Conventional treatments for insomnia include drugs targeting gamma-aminobutyric acid type-A (GABA-A), serotonin, histamine, or melatonin receptors; however, undesirable side effects are frequently reported, such as next-morning residual sleepiness, motor incoordination, falls, memory and cognitive impairment. Novel drugs that target orexin receptors gained increasing attention after discovering the role of orexin signalling pathway in wakefulness and , an orexin receptor antagonist that improved sleep. Daridorexant was designed via an intensive drug discovery program to improve the potency and maximize the duration of action while minimizing next-morning residual activity. Daridorexant works on orexin receptors OX1R and OX2R to block the binding of orexins, which are wake-promoting neuropeptides and endogenous ligands to these receptors. Daridorexant reduces overactive wakefulness: in the investigational trials, daridorexant reportedly improved sleep and daytime functioning in patients with insomnia. It was approved by the FDA on January 10, 2022, under the name QUVIVIQ. as the second orexin receptor antagonist approved to treat insomnia following . Daridorexant was approved by the European Commission on May 3, 2022 as the first dual orexin receptor antagonist approved in the market.

Indications:

This drug is primarily indicated for: In the US and Europe, daridorexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The European prescribing information states that insomnia should be characterized by symptoms that are present for at least 3 months and considerable impact on daytime functioning. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Daridorexant undergoes metabolic processing primarily in: Daridorexant undergoes extensive metabolism primarily mediated by CYP3A4 (89%), mostly via oxidative transformations. Other CYP enzymes individually contribute to less than 3% of metabolic clearance of daridorexant. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Daridorexant are crucial for its therapeutic efficacy: Daridorexant reaches peak plasma concentrations within one to two hours. Daridorexant has an absolute bioavailability of 62%. While a high-fat and high-calorie meal delayed the Tmax by 1.3 hours and decreased the Cmax by 16% in healthy subjects, the total exposure (AUC) was not affected. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Daridorexant is an important consideration for its dosing schedule: The terminal half-life is approximately 8 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Daridorexant exhibits a strong affinity for binding with plasma proteins: Daridorexant is 99.7% bound to plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Daridorexant from the body primarily occurs through: The primary route of excretion is via feces, accounting for approximately 57% of drug excretion. About 28% of the drug is excreted via urine primarily in the form of metabolites. Trace amounts of the parent drug were found in feces and urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Daridorexant is distributed throughout the body with a volume of distribution of: Daridorexant has a volume of distribution of 31 L. The blood to plasma ratio is 0.64. It effectively passes the blood-brain barrier. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Daridorexant is a critical factor in determining its safe and effective dosage: There is limited information on clearance. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Daridorexant exerts its therapeutic effects through: Daridorexant binds to and antagonizes the orexin receptors OX1R and OX2R (Ki = 0.47 and 0.93 nM, respectively) equipotentally. In clinical trials, daridorexant improved sleep onset and sleep maintenance, and patient-reported total sleep time. Patient-reported daytime sleepiness was also reportedly reduced. At a dose four times the maximum recommended dose, daridorexant does not prolong the QTc interval to any clinically relevant extent. Daridorexant is currently being assessed for a controlled substance schedule in the US. In a human abuse potential study, daridorexant showed some abuse potential at doses higher than the recommended dose (100-150 mg), indicated by similar “drug liking” ratings to zolpidem (30 mg) and suvorexant in recreational sedative drug users. However, at clinically relevant concentrations, daridorexant does not bind to abuse-associated CNS targets. In animal studies and clinical trials evaluating physical dependence, chronic administration of daridorexant did not produce withdrawal signs or symptoms upon drug discontinuation, indicating that the drug does not produce physical dependence. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Daridorexant functions by: The sleep and wake cycle is regulated by complex interactions between sleep-promoting systems, including inhibitory GABA activity, and wake-promoting systems, including orexins, acetylcholine and monoaminergic systems. Orexin, also called hypocretin, is a wake-promoting neuropeptide produced by a small group of neurons in the lateral hypothalamus. Orexin stabilizes wakefulness by activating orexin neurons with the highest activity during active wakefulness and minimal activity during sleep. Orexin neurons project to other wake-promoting neurons that also express orexin receptors: these include the histaminergic neurons of the tuberomammillary nucleus, noradrenergic neurons of the locus coeruleus, serotoninergic neurons of the dorsal raphe, dopaminergic neurons of the ventral tegmental area, and cholinergic neurons of the basal forebrain and the pedunculopontine and laterodorsal tegmental nuclei. These wake-promoting neurons are part of the ascending reticular activating system that operates under a feedback loop in the sleep and wake cycle. There are two identified types of orexin (OXA and OXB) that bind to orexin type 1 and 2 receptors (OX1R and OX2R), which are G-protein coupled receptors. OXA binds more preferentially to OX1R, while OX2R shows a dual affinity for OXA and OXB. The defined role of each orexin receptor is still unclear; however, there is some evidence suggesting that OX2R regulates sleep and wake, while OX1R have some role in sleep maintenance. Daridorexant blocks the binding of wake-promoting neuropeptides OXA and OXB to OX1R and OX2R, thereby suppressing wake drive. Daridorexant selectively targets orexin neurons and inhibits downstream neuronal pathways that promote wakefulness; however, it does not affect neuronal pathways that cause side effects commonly seen in positive allosteric GABA-A receptor modulators. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Daridorexant is categorized under the following therapeutic classes: Central Nervous System Depressants, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Orexin Receptor Antagonists, Wakefulness-Promoting Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.