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General Description:

Lemborexant, identified by CAS number 1369764-02-2, is a notable compound with significant therapeutic applications. Lemborexant is a novel dual orexin receptor antagonist used in the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Recent research in the field of sleep disorders has revealed that insomnia is likely driven not by the inability of the brain to "switch on" sleep-related circuits, but rather an inability to "switch-off" wake-promoting circuits. Whereas historically popular pharmacologic treatments for insomnia (e.g. , , benzodiazepines) focus on enhancing sleep drive via modulation of GABA and melatonin receptors, lemborexant and other orexin antagonists (e.g. ) act to counteract inappropriate wakefulness. This novel mechanism of action offers potential advantages over classic hypnotic agents, including a more favorable adverse effect profile and potentially greater efficacy, and may signal the beginning of a new wave of treatment options for patients suffering from insomnia.

Indications:

This drug is primarily indicated for: Lemborexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lemborexant undergoes metabolic processing primarily in: Given that less than 1% of an administered dose is recovered unchanged in the urine, it is likely that lemborexant is extensively metabolized - this has been confirmed in rat and monkey models, but its metabolism in humans has not been fully characterized. Prescribing information states that it is predominantly metabolized by CYP3A4, with a smaller contribution by CYP3A5. The major circulating metabolite is lemborexant's M10 metabolite, which is pharmacologically active and binds to orexin receptors with a similar affinity to the parent drug. The M10 metabolite has the potential to induce CYP3A and CYP2B6 enzymes, weakly inhibit CYP3A enzymes, and is a substrate of P-gp transporters. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lemborexant are crucial for its therapeutic efficacy: Animal models of lemborexant disposition have demonstrated rapid absorption following oral administration. The T_max of lemborexant is approximately 1-3 hours, or 3-5 hours following administration of a high-fat, high-calorie meal. C_max and AUC_0-24h increase at a rate slightly less than proportionate to the given dose. Following administration of a high-fat, high-calorie meal, C_max is decreased by 23% and AUC_0-inf is increased by 18%. AUC, C_max, and terminal half-life are increased in the presence of moderate hepatic impairment, and AUC (but not half-life) is increased in the presence of mild hepatic impairment. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lemborexant is an important consideration for its dosing schedule: The half-life for lemborexant at doses of 5mg and 10mg is 17 and 19 hours, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lemborexant exhibits a strong affinity for binding with plasma proteins: Lemborexant is approximately 94% protein-bound _in vitro_, though the specific proteins to which it binds in plasma have not been elucidated. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lemborexant from the body primarily occurs through: Following oral administration, 57.4% of the dose is found in the feces and 29.1% in the urine. Less than 1% of the dose recovered in the urine exists as unchanged parent drug, suggesting extensive metabolism. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lemborexant is distributed throughout the body with a volume of distribution of: The volume of distribution of lemborexant is 1970 L, indicating extensive tissue distribution. This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Lemborexant exerts its therapeutic effects through: Lemborexant promotes sleep by antagonizing the actions of wake-promoting chemicals in the brain. Episodes of complex sleep behaviors (e.g. eating food, having sex, making phone calls) have been reported in patients using lemborexant - these events may occur in hypnotic-naive and hyponotic-experienced patients, and patients are unlikely to remember these events. Patients exhibiting complex sleep behaviors should discontinue lemborexant immediately. Lemborexant may carry some risk of abuse, and should be used with caution in patients with a history of alcohol or drug addiction. Its controlled substance schedule is currently under review by the Drug Enforcement Administration. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lemborexant functions by: The orexin neuropeptide signaling system is involved in many physiologic functions, including sleep/wake control. Orexin-A and orexin-B activate post-synaptic G-protein coupled orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are found on neurons in the hypothalamus that project to numerous wake-controlling nuclei. Each receptor carries slightly different activity - activation of OX1R appears to suppress the onset of rapid eye movement (REM) sleep, whereas activation of OX2R appears to suppress non-REM sleep. Lemborexant is an competitive antagonist of OX1R and OX2R. By blocking the binding of wake-promoting orexin-A and -B at these receptors, lemborexant suppresses the wake-drive, thereby promoting sleep. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Lemborexant belongs to the class of organic compounds known as n-arylamides. These are organic compounds that contain a carboxamide group that is N-linked to a aryl group. They have the generic structure RC(=O)N(R')H, R = organyl group and R'= aryl group, classified under the direct parent group N-arylamides. This compound is a part of the Organic compounds, falling under the Organic nitrogen compounds superclass, and categorized within the Organonitrogen compounds class, specifically within the N-arylamides subclass.

Categories:

Lemborexant is categorized under the following therapeutic classes: Central Nervous System Agents, Central Nervous System Depressants, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Hypnotics and Sedatives, Nervous System, Neurotransmitter Agents, Orexin Receptor Antagonists, P-glycoprotein substrates, Psycholeptics, Sleep Aids, Pharmaceutical, Sleep Initiation and Maintenance Disorders. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.