Ueno Takashi, Ishida Tomomi, Aluri Jagadeesh, Suzuki Michiyuki, Beuckmann Carsten T, Kameyama Takaaki, Asakura Shoji, Kusano Kazutomi
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.).
Drug Metab Dispos. 2021 Jan;49(1):31-38. doi: 10.1124/dmd.120.000229. Epub 2020 Nov 3.
Lemborexant is a novel dual orexin receptor antagonist recently approved for the treatment of insomnia in the United States and Japan. Here, disposition and metabolic profiles were investigated in healthy human subjects. After single oral administration of 10 mg [C]lemborexant (100 µCi), plasma concentrations of lemborexant and radioactivity peaked at 1 hour postdose and decreased biphasically. Cumulative recovery of the administered radioactivity within 480 hours was 86.5% of the dose, with 29.1% in urine and 57.4% in feces. Unchanged lemborexant was not detected in urine but accounted for 13.0% of the dose in feces, suggesting that the main elimination pathway of lemborexant was metabolism. Metabolite analyses revealed that the major metabolic pathways of lemborexant are oxidation of the dimethylpyrimidine moiety and subsequent further oxidation and/or glucuronidation. In plasma, lemborexant was the dominant component, accounting for 26.5% of total drug-related exposure. M4, M9, M10, and M18 were detected as the major radioactive components; M10 was the only metabolite exceeding 10% of total drug-related exposure. Although M4, M9, and M10 showed binding affinity for orexin receptors comparable to that of lemborexant, their contributions to the sleep-promoting effects of lemborexant are likely low because of the limited brain penetration by P-glycoprotein. Exposure comparison between humans and nonclinical toxicology species confirmed that plasma exposure of M10 was higher in at least one animal species compared with that in humans, indicating that there is no disproportionate metabolite in humans, as defined by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use M3(R2) and U.S. Food and Drug Administration Metabolite in Safety Testing guidance; therefore, no additional toxicology studies are needed. SIGNIFICANCE STATEMENT: This study provides detailed data of the disposition and metabolism of lemborexant, a novel therapeutic drug for insomnia, in humans, as well as a characterization of the circulating metabolites and assessment of their contributions to efficacy and safety. The information presented herein furthers our understanding of the pharmacokinetic profiles of lemborexant and its metabolites and will promote the safe and effective use of lemborexant in the clinic.
伦博瑞生是一种新型的双重食欲素受体拮抗剂，最近在美国和日本被批准用于治疗失眠。在此，对健康人类受试者的处置和代谢情况进行了研究。单次口服10毫克[C]伦博瑞生（100微居里）后，伦博瑞生的血浆浓度和放射性在给药后1小时达到峰值，并呈双相下降。480小时内给药放射性的累积回收率为剂量的86.5%，其中29.1%经尿液排出，57.4%经粪便排出。尿液中未检测到未变化的伦博瑞生，但粪便中其占剂量的13.0%，这表明伦博瑞生的主要消除途径是代谢。代谢物分析显示，伦博瑞生的主要代谢途径是二甲基嘧啶部分的氧化以及随后的进一步氧化和/或葡萄糖醛酸化。在血浆中，伦博瑞生是主要成分，占总药物相关暴露量的26.5%。M4、M9、M10和M18被检测为主要放射性成分；M10是唯一超过总药物相关暴露量10%的代谢物。尽管M4、M9和M10对食欲素受体的结合亲和力与伦博瑞生相当，但由于P-糖蛋白对大脑的穿透有限，它们对伦博瑞生促睡眠作用的贡献可能较低。人与非临床毒理学物种之间的暴露比较证实，与人类相比，至少有一种动物物种中M10的血浆暴露量更高，这表明按照国际人用药品技术协调理事会M3(R2)和美国食品药品监督管理局《安全性测试中的代谢物》指南的定义，人类中不存在不成比例的代谢物；因此，无需进行额外的毒理学研究。意义声明：本研究提供了新型失眠治疗药物伦博瑞生在人体中的处置和代谢的详细数据，以及循环代谢物的特征及其对疗效和安全性贡献的评估。本文提供的信息进一步加深了我们对伦博瑞生及其代谢物药代动力学特征的理解，并将促进伦博瑞生在临床上的安全有效使用。
