렘보렉산트

DEA Schedule IV Controlled Substance -> Depressants

Pharmaceuticals -> Unknown

Pharmaceuticals -> Listed in ZINC15

Breast Feeding; Lactation; Milk, Human; Hypnotics and Sedatives; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

In several clinical trials, lemborexant was found to be well tolerated, with serum ALT elevations above 3 times the upper limit of normal in less than 1% of treated subjects and with similar rates in placebo recipients. The elevations were transient and asymptomatic, none required dose modification or discontinuation, and none were associated with a simultaneous elevation in serum bilirubin. Thus, in the registration trials of lemborexant, there were no reports of clinically apparent liver injury. Since its approval and more widespread use, lemborexant has been available has not been implicated in causing cases of clinically apparent liver injury.

Clinical evidence to support toxic doses of lemborexant in humans is scarce. In at least one clinical study, 7.5 times the recommended dose of lemborexant was given to healthy human subjects resulting in dose-dependent increases of somnolence frequency, providing little information regarding toxicity. There is no specific antidote to lemborexant overdose. In the case of a suspected overdose, the protocol of any drug overdose should be followed, with close monitoring from a medical professional.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Lemborexant

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

N - Nervous system

QN - Nervous system

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 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.

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.