Lemborexant 10 mg · Tablets

The mechanism of action of lemborexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

Following single doses of lemborexant 2.5 to 75 mg, geometric mean Cmax and AUC0-24h increased slightly less than in proportion to dose. The extent of accumulation of lemborexant at steady-state is 1.5- to 3-fold across this dose range.

Absorption — The time to peak concentration (tmax) of lemborexant is approximately 1 to 3 hours.

Effect of Food — Lemborexant Cmax decreased by 23%, AUC0-inf increased by 18%, and tmax was delayed by 2 hours following administration of a high-fat and high-calorie meal (containing approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively).

Distribution — The volume of distribution of lemborexant is 1970 L. Plasma protein binding of lemborexant is approximately 88% in vitro and 94% in clinical samples. The blood to plasma concentration ratio of lemborexant is 0.65.

Metabolism — Lemborexant is primarily metabolized by CYP3A4, and to a lesser extent by CYP3A5. The major circulating metabolite is M10.

Excretion — Following administration of an oral dose, 57.4% of the dose was recovered in the feces and 29.1% in the urine (<1% as unchanged). The effective half-life for lemborexant 5 mg and 10 mg is 17 and 19 hours, respectively.

Specific Populations — No clinically significant differences in the pharmacokinetics of lemborexant were observed based on age, sex, race/ethnicity, or body mass index. No studies have been conducted to investigate the pharmacokinetics of lemborexant in pediatric patients. Exposures of lemborexant in patients with hepatic and renal impairment are summarized in Figure 1.

Drug Interaction Studies — The effects of other drugs on the exposures of lemborexant are summarized in Figure 2. The effects of lemborexant on the exposures of other drugs are summarized in Figure 3. Based on these results, drug interactions between lemborexant and strong CYP3A inducers, strong CYP3A inhibitors, moderate CYP3A inhibitors, and CYP2B6 substrates are clinically significant [see Dosage and Administration ( 2.2 ), Drug Interactions ( 7.1 )].

Physiologically-based pharmacokinetic (PBPK) modeling predicted that concomitant use of weak CYP3A inhibitors increased lemborexant exposure by less than 2-fold [see Dosage and Administration ( 2.2 ), Drug Interactions ( 7.1 )], and that lemborexant is expected to have minimal effect on the pharmacokinetics of CYP2C8, CYP2C9, or CYP2C19 substrates.

In Vitro Studies — In vitro metabolism studies demonstrated that lemborexant and M10 have the potential to induce CYP3A and a weak potential to inhibit CYP3A and induce CYP2B6. Lemborexant and M10 do not inhibit other CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) or transporters (P-gp, BCRP, BSEP, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, and MATE2-K). Lemborexant and M10 do not induce CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations.

Lemborexant is a potential poor substrate of P-gp, but M10 is a substrate of P-gp. Lemborexant and M10 are not substrates of BCRP, OATP1B1, or OATP1B3.