Eisai Ltd., Hatfield, United Kingdom.
Eisai Inc., Woodcliff Lake, NJ, USA.
Pharmacol Res Perspect. 2021 Apr;9(2):e00758. doi: 10.1002/prp2.758.
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 [C ] and area under the curve extrapolated to infinity [AUC ]) increased by ~58% (C ) and ~25% (AUC ) in subjects with mild HI and ~22% (C ) and ~54% (AUC ) 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.
雷美替胺是一种双重食欲素受体拮抗剂，已获美国、日本和加拿大批准用于治疗成人失眠症。这项 I 期、多中心、开放性、平行组研究评估了轻度或中度肝损伤（HI）对雷美替胺药代动力学和代谢的影响。在轻度（Child-Pugh 分级 A）或中度（Child-Pugh 分级 B）HI 以及年龄、性别和体重指数（BMI）匹配的健康对照受试者（每组 8 例）中评估了雷美替胺的药代动力学、耐受性和安全性。受试者单次口服雷美替胺 10mg（LEM10）。在给药后 312 小时内采集血样，以评估雷美替胺的药代动力学。所有组的中位达峰时间相似。与健康受试者相比，轻度 HI 受试者的暴露量（最大血浆浓度 [C ]和从无穷远处外推的曲线下面积 [AUC ]）分别增加了约 58%（C ）和 25%（AUC ），中度 HI 受试者分别增加了约 22%（C ）和 54%（AUC ）。与健康受试者相比，轻度和中度 HI 受试者的清除率分别下降了 20%和 35%。所有治疗相关不良事件（TEAEs）的严重程度均为轻度；未发生严重 TEAEs。总之，单次给予 LEM10 后，轻度 HI 受试者的雷美替胺暴露量与健康受试者相似，中度 HI 受试者的暴露量增加。轻度 HI 受试者无需调整剂量。中度 HI 受试者的剂量应限制在 5mg。所有组均耐受良好。
