Lemborexant – Mechanism of Action | Psychopharmacology | Clinical Application

MECHANISM OF ACTION OF LEMBOREXANT

We have covered the neurobiology of sleep in more detail earlier.

Wakefulness: 

• Wakefulness is promoted through the activity of groups of monoaminergic cells such as the raphe nuclei (RN), locus coeruleus (LC) and tuberomammillary nucleus (TMN). These neurons inhibit sleep-promoting neurons in the Ventrolateral preoptic nucleus (VLPO), which relieves inhibition of the monoaminergic cells and Orexin (ORX) neurons. These monoaminergic nuclei also directly stimulate wakefulness.
• In addition, ORX neurons act to promote the activity of monoaminergic nuclei. As the VLPO neurons do not have ORX receptors, the ORX neurons reinforce the monoaminergic tone rather than directly inhibiting the VLPO, increasing wakefulness.

Sleep:

• Sleep is maintained by the activity of the VLPO neurons as they inhibit the monoaminergic nuclei and thereby relieve their inhibition.
• This relief, in turn, enables VLPO neurons to inhibit ORX neurons, which further prevents any activation of monoaminergic nuclei that might interrupt sleep.

Mechanism of action of Lemborexant to promote sleep: 

Lemborexant is a competitive antagonist of post-synaptic G-protein coupled orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are found in the hypothalamus and project to wake-controlling nuclei in the cerebral cortex, cingulate cortex, nucleus accumbens, dorsal raphe, locus coeruleus, and paraventricular thalamus among others. [Sun et al. 2021]

This is important because the orexin neuropeptide signalling system has a vital role in regulating arousal states.

OX2R has a similar high affinity for both orexin peptides (A and B), whereas OX1R has a greater binding affinity to orexin-A but a much lower affinity for orexin B.

When activated, the role of OX1R is to suppress REM sleep, and the role of OX2R is to suppress both non-REM sleep and REM sleep. Lemborexant enables sleep by preventing activation of OX1R and OX2R.

Lemborexant blocks the binding of wake-promoting orexin-A and B at OX1R and OX2R receptors and suppresses the maintenance of wakefulness, thereby promoting sleep.

PHARMACOKINETICS OF LEMBOREXANT

Following oral administration, lemborexant is rapidly absorbed and has a Tmax of approximately 1–3 hours if the patient is in a fasted state; however, it has been demonstrated that this will extend to 3–5 hours after a high-fat, high-calorie meal. [Ueno et al. 2019]

Furthermore, after a high-fat, high-calorie meal, the Cmax is reduced by 23%. Lemborexant at doses of 5 mg and 10 mg have a half-life of 17 and 19 hours, respectively. [DAYVIGO Prescribing Information]

Metabolism by CYP3A is the major elimination pathway of lemborexant. Hence CYP3A inhibitors and inducers can affect the levels of Lemborexant.

The route of elimination is via the faeces (57.4% of the dose) and urine (29.1% of the dose) with <1% of the dose unchanged, which is suggestive of extensive metabolism.

DOSING OF LEMBOREXANT

• The recommended dose of Lemborexant (DAYVIGO) is 5 mg, taken no more than once per night and within a few minutes before going to bed, with at least 7 hours remaining before the planned time of awakening.
• If the 5 mg dose is well-tolerated, but a more significant effect is needed, the dose can be increased to 10 mg once daily, the maximum recommended dose.
• Lemborexant should be used at the lowest dose and the shortest duration as clinically indicated.
• Time to sleep onset may be delayed if taken with or soon after a meal

If insomnia does not remit after 7 to 10 days of treatment, consider a complete evaluation for insomnia.

Insomnia – Neurobiology | Pathophysiology | Assessment and Management

Worsening insomnia or the emergence of new cognitive or behavioural abnormalities after initiation of lemborexant may indicate an unrecognised underlying psychiatric or medical disorder.

SAFETY PROFILE AND DRUG INTERACTIONS

Clinical trial experience shows that lemborexant 5 mg and 10 mg are well tolerated with a low discontinuation rate due to adverse reactions of 1.4% and 2.6%. [Rosenberg et al. 2019]

Somnolence was the most common adverse event reported in ≥5% of patients with other adverse events (≥2%), including fatigue, headache, nightmares or abnormal dreams. [DAYVIGO Prescribing Information]

Lemborexant is not associated with physical dependence.

Lemborexant is contraindicated in patients with narcolepsy.

Safety in children and pregnancy is not known.

Drug interactions:

Lemborexant is likely extensively metabolised by the CYP isoenzyme system, given that <1% is recovered. However, its metabolism in humans is currently unknown as the data at present comes from rat and monkey models. [Ueno et al. 2019]

It appears lemborexant is predominantly metabolised by CYP3A4, although there is a small contribution from CYP3A5. [DAYVIGO Prescribing Information]

• Lemborexant’s major circulating metabolite is called M10, which is pharmacologically active with a similar binding capacity and affinity as lemborexant
• Other metabolites (M4, M9, and M18) have been detected; however, none of these exceeded 10% of the total drug-related exposure

Physiologically based pharmacokinetic models predict that the M10 metabolite can induce CYP3A4 and CYP2B6 and potentially weakly inhibit CYP3A enzymes. [Ueno et al. 2021a] In vitro metabolism studies have also reported interactions with P-glycoprotein transporters. [Ueno et al. 2021b]

Alcohol should not be consumed with lemborexant as it increases the Cmax and can potentiate the sedative side effects.

CLINICAL EVIDENCE

Lemborexant is effective for treating insomnia disorder, with significant benefits on sleep onset and sleep maintenance. [Kärppä et al. 2020]

Lemborexant is an effective option for patients who cannot tolerate most commonly prescribed medications for insomnia, such as benzodiazepines and sedative-hypnotics (Z drugs). It may be particularly useful in geriatric patients sensitive to side effects. [Waters, 2022]

There have been concerns raised that the use of sleep-promoting drugs, in general, can impair driving ability the day after their administration. Therefore, a randomised, double-blind, double-dummy, placebo and active-controlled study design was used in accordance with the FDA’s guiding requirements. [Vermeeren et al. 2019]

• Driving performance is assessed using a standardised highway driving test that measures the standard deviation of lateral position (SDLP) and is an indicator of vehicle control and lane weaving (measured in centimetres). [Vinckenbosch et al. 2020]

This study showed that 9-hours after administering lemborexant 2.5, 5, and 10 mg, the mean drug–placebo changes were small (0.02 cm, 0.23 cm, and 0.73 cm, respectively) and well below the impairment threshold of 2.4 cm. [Vermeeren et al. 2019] In contrast, 7.5 mg zopiclone had a statistically significant and clinically meaningful mean drug–placebo change of 2.04 cm.

A summary of 9 clinical studies further indicated that lemborexant did not substantially impair next-day functioning among healthy subjects and subjects with insomnia. [Moline et al., 2021]

SUMMARY

Therapeutics targeting the orexin receptors for the treatment of sleep disorders represent a relatively new class in the treatment of insomnia. Several other DORAs are in clinical development and their results are expected to shed light on how they specifically modulate specific sleep states.