Mechanism of Action of Lemborexant
Lemborexant is a dual orexin receptor antagonist that works by competitively and reversibly blocking both orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), with stronger inhibitory effects on OX2R, thereby suppressing the wake-promoting effects of orexin neuropeptides and facilitating physiological sleep. 1, 2
Detailed Pharmacological Mechanism
Orexin System Background
- Orexin (also called hypocretin) is a neuropeptide produced in the lateral hypothalamic area that serves as a key mediator controlling the sleep-wake state 1
- The orexin system promotes wakefulness and arousal through activation of two G-protein coupled receptors: OX1R and OX2R 1, 2
Receptor Binding Characteristics
- Lemborexant exhibits reversible competitive antagonism at both OX1R and OX2R, with greater affinity for OX2R compared to OX1R 1, 2
- The drug binds to and dissociates from orexin receptors rapidly, which means the pharmacokinetics of blood concentration directly impacts its pharmacological action 1
- This rapid binding and dissociation profile distinguishes lemborexant from other orexin antagonists and contributes to its clinical profile 1
Physiological Sleep Induction
- By blocking orexin receptors, lemborexant is thought to induce physiological sleep by acting specifically on the sleep-wake cycle rather than through generalized CNS depression 1
- In preclinical rat studies, lemborexant exhibited sleep-inducing effects without altering sleep architecture, suggesting preservation of normal sleep stages 1
- This mechanism differs fundamentally from GABA receptor agonists (benzodiazepines and Z-drugs), which work through enhancement of inhibitory neurotransmission 3
Clinical Pharmacology Supporting the Mechanism
Pharmacokinetic Profile
- Time to maximum concentration ranges from approximately 1 to 3 hours for the 5 mg and 10 mg doses 4
- The mean effective half-life is 17 hours for lemborexant 5 mg and 19 hours for lemborexant 10 mg 4, 5
- Plasma concentration at 9 hours post-dose is 27% of maximum concentration following multiple dosing with lemborexant 10 mg, explaining minimal next-morning residual effects 4
Metabolism
- Lemborexant is metabolized primarily by CYP3A4/5 enzymes 5
- There are no significant effects of age, sex, or weight on lemborexant pharmacokinetics 4, 5
Comparison to Other Orexin Antagonists
- Lemborexant is similar to suvorexant (another dual orexin receptor antagonist) but has a longer half-life (17-19 hours versus 12 hours for suvorexant) 5
- The stronger affinity for OX2R compared to OX1R may contribute to its efficacy profile, as OX2R is considered more critical for sleep-wake regulation 1, 2