In healthy patients, the pharmacokinetic profile of lemborexant was examined after single doses of up to 200 mg and after once-daily administration of up to 75 mg for 14 days. Lemborexant is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 to 3 hours. Lemborexant exhibits linear pharmacokinetics with multi-exponential decline in plasma concentrations. The extent of accumulation of lemborexant at steady-state is 1.5- to 2-fold across the dose range. The effective half-life for 5 mg and 10 mg is 17 and 19 hours respectively. The plasma concentration at 9 hours after administration is approximately 10% to 13% of the Cmax.
Ingestion of lemborexant with a high-fat meal resulted in a decrease in the rate of absorption as demonstrated by 23% decrease in Cmax and delay in tmax of 2 hours and 18% increase in total exposure AUC.
Time to sleep onset may be delayed if taken with or soon after a meal.
The volume of distribution of lemborexant is 1970 L. Plasma protein binding of lemborexant in clinical samples is approximately 94%. The blood to plasma concentration ratio of lemborexant is 0.65.
In vitro binding of lemborexant and its major circulating metabolite, M10 (the N-oxide of lemborexant) to human plasma proteins ranged from 87.4% to 88.7% and 91.5% to 92.0%, respectively, at concentrations of 100 to 1000 ng/mL. At these concentrations in vitro, lemborexantwas bound primarily to human serum albumin, low-density lipoprotein, and high-density lipoprotein. In vitro blood to plasma concentration ratios of lemborexant and M10 in humans were 0.610 to 0.656 and 0.562 to 0.616, respectively, at concentrations of 100 to 1000 ng/mL.
Lemborexant is primarily metabolized by CYP3A4, and to a lesser extent by CYP3A5. M10 is the only major circulating metabolite (12% of parent). The contribution of this metabolite to the pharmacologic activity of lemborexant is considered to be minimal.
The primary route of elimination is through the feces, with 57.4% of radiolabeled dose recovered in the feces and 29.1% in the urine. The percent of lemborexant excreted unchanged in the urine is negligible (<1% dose). The effective half-life of lemborexant 5 mg and 10 mg is 17 and 19 hours respectively.
Age, Sex, Race/Ethnicity and BMI
No clinically significant differences in the pharmacokinetics of lemborexant were observed based on age, sex, race/ethnicity, or body mass index.
Based on a population pharmacokinetic analysis in patients receiving 5 or 10 mg lemborexant once daily, apparent clearance was 26% lower in elderly (>65 years of age). However, this effect was not clinically relevant.
No studies have been conducted to investigate the pharmacokinetics of lemborexant in pediatric patients.
Patients with Renal Impairment
Severe renal impairment (urinary creatinine clearance ≤30 mL/min/1.73m2) increased Lemborexant exposure (AUC) 1.5-fold but had no effect on Cmax. No dose adjustment is required in patients with renal impairment.
Patients with Hepatic Impairment
Lemborexant has not been studied in patients with severe hepatic impairment. Use in this population is not recommended. Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic insufficiency increased lemborexant AUC and Cmax by 1.5-fold. Terminal half-life was only increased in patients with moderate hepatic impairment (Child-Pugh class B). No relationship between these findings and hepatic function was observed. Exposures of lemborexant in patients with hepatic and renal impairment are summarized in Figure 1.
Figure 1. Effects of Hepatic and Renal Impairment on Lemborexant Pharmacokinetics
Drug Interaction Studies
Effects of Other Drugs on Lemborexant
The effects of other drugs on the pharmacokinetics of lemborexant (10 mg) are presented in Figure 2 as change relative to lemborexant alone (test/reference). Based on these results, drug interactions between lemborexant and strong CYP3A inducers, strong CYP3A inhibitors, and moderate CYP3A inhibitors are clinically significant. Using a physiologically based pharmacokinetic (PBPK) model, a weak effect is predicted when weak CYP3A inhibitors (e.g.,fluoxetine) are co-administered with lemborexant. Coadministration of moderate (e.g., fluconazole) or strong (e.g., itraconazole) CYP3A inhibitors significantly increased lemborexant exposure. CYP3A inducers (e.g., rifampin) significantly decreased Lemborexant exposure.
There was no evidence of an additive effect on impairing postural stability (as evidenced by body sway) when lemborexant was co-administered with alcohol; lemborexant did not impact postural stability when dosed alone. An additive negative effect on cognitive performance was observed up to 6 hours post dose when lemborexant 10 mg was co-administered with a single dose of alcohol (0.6 g/kg for females and 0.7 g/kg for males).
Co-administration of an H2 blocker (famotidine) with lemborexant decreased Cmax by 27% and delayed tmax by 0.5 hours, but had no statistically significant effect on overall lemborexant exposure (AUC). A population analysis of Phase 1-3 data also showed no effect of proton pump inhibitors (PPIs) on apparent clearance of lemborexant. A pooled analysis conducted on patients with a medical history of gastroesophageal reflex disease (GERD) or taking PPIs or H2 blockers in Study 303 and 304 showed that there was no effect on sleep latency or on safety parameters. Thus lemborexant can be co-administered with gastric acid-reducing agents (PPIs or H2 blockers).
Co-administration of an oral contraceptive containing norethindrone (NE) and ethinyl estradiol (EE) with lemborexant had no statistically significant effect on lemborexant pharmacokinetics.
Figure 2. Effects of Co-administered Drugs on the Pharmacokinetics of Lemborexant 10 mg
Effects of Lemborexant on Other Drugs
In vitro metabolism studies demonstrated that lemborexant and M10 have a potential to induce CYP3A and a weak potential to inhibit CYP3A and induce CYP2B6. Lemborexant and M10 do not have the potential to inhibit other CYP isoforms 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 poor substrate of P-gp, but M10 is a substrate of P-gp. Lemborexant and M10 are not substrates of BCRP, OATP1B1, or OATP1B3.
Specific in vivo effects of lemborexant (10mg) on the pharmacokinetics of bupropion, oral contraceptives, and midazolam are presented in Figure 3 as a change relative to the interacting drug administered alone (test/reference). Based on these results, drug interactions between lemborexant and CYP2B6 substrates are clinically significant. Lemborexant is expected to have minimal effect on the pharmacokinetics of CYP2C8, CYP2C9, or CYP2C19 substrates.
Co-administration of an oral contraceptive containing norethindrone (NE) and ethinyl estradiol (EE) with lemborexant (10 mg) did not affect the Cmax and AUC of NE or the Cmax of EE, and increased AUC of EE by 13%. This latter small change is not considered clinically relevant.
Clinical studies with substrates of CYP3A or CYP2B6: Despite the in vitro findings, lemborexant does not induce or inhibit CYP3A4. Lemborexant weakly induces CYP2B6 (e.g., bupropion is CYP2B6 substrate). CYP3A and CYP2B6 substrates can be co-administered with lemborexant.
Figure 3. Effects of Lemborexant 10 mg on the Pharmacokinetics of Co-administered Drugs