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

Pharmacology Research & Perspectives

Gleb Filippov¹  Jagadeesh Aluri¹  Margaret Moline¹  Ishani Landry¹  Larisa Reyderman¹  Nancy Hall¹  Satish Dayal² 

[1] Eisai Inc. Woodcliff Lake NJ USA;Eisai Ltd. Hatfield United Kingdom;

关键词: drug safety;    dual orexin receptor antagonist;    hepatic impairment;    lemborexant;    pharmacokinetics;   

DOI  :  10.1002/prp2.758

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown