Effect of hepatic impairment on pharmacokinetics, safety, and tolerability of lemborexant.

Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open-label, parallel-group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) HI and healthy age-, sex-, and body mass index (BMI)-matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax ] and area under the curve extrapolated to infinity [AUC0-inf ]) increased by ~58% (Cmax ) and ~25% (AUC0-inf ) in subjects with mild HI and ~22% (Cmax ) and ~54% (AUC0-inf ) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060-0.065). All treatment-emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups.

Dayal S ，Aluri J ，Hall N ，Filippov G ，Moline M ，Reyderman L ，Landry I ... -  《Pharmacology Research & Perspectives》

Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant.

The primary aim of this study was to examine the effect of severe renal impairment (SRI) on the pharmacokinetics of lemborexant, a dual orexin receptor antagonist indicated for the treatment of insomnia. A phase 1 multicenter, single-dose, open-label, parallel-group study was conducted in subjects with SRI not requiring dialysis (estimated glomerular filtration rate 15-29 ml/min/1.73 m2 ; n = 8) compared with demographically matched healthy subjects with normal renal function (n = 8). Plasma levels of lemborexant and its metabolites were measured over 240 h following a single oral 10-mg dose administered in the morning. Relative to subjects with normal renal function, lemborexant maximum plasma concentration (Cmax ) was similar, whereas area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUC(0-t) ) and AUC from zero to infinity (AUC(0-inf) ) were about 1.5-fold higher in subjects with SRI. The geometric mean ratios (90% confidence interval) were 104.8 (77.4-142.0), 150.5 (113.2-200.3), and 149.8 (113.1-198.6) for Cmax , AUC(0-t) , and AUC(0-inf) , respectively. In both groups, the median lemborexant time to Cmax (tmax ) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax was reduced ~20% and exposure (AUC(0-t) and AUC(0-inf) ) was ~1.4- to 1.5-fold higher in subjects with SRI versus healthy subjects; tmax was delayed ~1.5-2 h for M4 and M10. All treatment-emergent adverse events were mild or moderate. Lemborexant pharmacokinetics were not sufficiently altered to warrant a dose adjustment for subjects with renal impairment.

Landry I ，Aluri J ，Hall N ，Filippov G ，Dayal S ，Moline M ，Reyderman L ... -  《Pharmacology Research & Perspectives》

Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder.

Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (Cav,ss ) to the probability of most frequent treatment-emergent adverse events (TEAEs). The 12 230-observation, 1892-subject PK data set included data from 12 clinical studies with predominantly female subjects (66%) ranging in age from 18 to 88 years and from 37 to 168 kg in body weight. The 1664-subject exposure-response data set included data from 3 late-stage studies. Lemborexant pharmacokinetics were described by a 3-compartment model with combined first- and zero-order absorption with lag time and linear elimination. Oral clearance decreased with increasing body mass index (exponent, -0.428), increasing alkaline phosphatase levels (exponent, -0.118), and was 26% lower in the elderly (≥65 years). Across the adverse event analysis, the frequency of subjects experiencing TEAEs during active treatment ranged from approximately 3% to 8%, in the range estimated for placebo. With and without adjustment for age, lemborexant exposure (Cav,ss ) was not a clinically meaningful linear predictor of the probability of specific TEAEs: somnolence, nasopharyngitis, flu/influenza, urinary tract infection, upper respiratory tract infection, or headache. Given the small effect sizes of covariates of the PK model and a low degree of association of lemborexant TEAEs and exposure over the range of phase 3 (therapeutic) 5- and 10-mg doses, lemborexant can be safely administered without the need for dose adjustment.

Lalovic B ，Majid O ，Aluri J ，Landry I ，Moline M ，Hussein Z ... -  《-》

Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial.

Lemborexant is a dual orexin receptor antagonist approved in the United States, Japan, and Canada for the treatment of insomnia in adults. We report effectiveness and safety outcomes in subjects with insomnia who received up to twelve months of continuous lemborexant treatment in Study E2006-G000-303 (Study 303; SUNRISE-2). Study 303 was a twelve-month, global, multicenter, randomized, double-blind, parallel-group, Phase 3 study divided into two treatment periods. In Treatment Period 1 (first six months), subjects (n = 949, Full Analysis Set) were randomized to daily placebo, lemborexant 5 mg (LEM5) or lemborexant 10 mg (LEM10). In Treatment Period 2 (second six months), placebo subjects were rerandomized to LEM5 or LEM10, and subjects randomized to lemborexant continued their assigned treatment (LEM5, n = 251; LEM10, n = 226). Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored. For all sleep parameters, the significant benefits observed with LEM5 and LEM10 versus placebo over six months were maintained at twelve months in subjects who received twelve continuous months of treatment. There was no evidence of rebound insomnia or withdrawal in either lemborexant group following treatment discontinuation. Over twelve months of lemborexant treatment, most TEAEs were mild/moderate; the most common TEAEs were nasopharyngitis, somnolence and headache. LEM5 and LEM10 had significant benefit on sleep onset and sleep maintenance compared with placebo, and importantly, lemborexant effectiveness persisted at twelve months, suggesting that lemborexant may provide long-term benefits for subjects with insomnia. ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Yardley J ，Kärppä M ，Inoue Y ，Pinner K ，Perdomo C ，Ishikawa K ，Filippov G ，Kubota N ，Moline M ... -  《-》

Effects of Lemborexant on the Pharmacokinetics of Oral Contraceptives: Results From a Phase 1 Drug-Drug Interaction Study in Healthy Females.

Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug-drug interaction study was conducted. This single-center, open-label, fixed-sequence study examined potential drug-drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18-44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady-state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment.

Landry I ，Aluri J ，Hall N ，Filippov G ，Dayal S ，Moline M ，Reyderman L ... -  《Clinical Pharmacology in Drug Development》