Eisai Co, Ltd, Tsukuba, Japan.
Eisai Co, Ltd, Tsukuba, Japan.
Regul Toxicol Pharmacol. 2021 Dec;127:105053. doi: 10.1016/j.yrtph.2021.105053. Epub 2021 Oct 4.
Lemborexant is a dual orexin receptor antagonist (DORA) approved in multiple countries including the United States, Japan, Canada and Australia for the treatment of adults with insomnia. As required for marketing approval of new compounds with central nervous system activity with sedating effects, the abuse potential of lemborexant was assessed in accordance with regulatory guidelines, which included three nonclinical studies. These assessments comprised physical dependence and drug discrimination studies in rats and a self-administration study in rhesus monkeys. There was no evidence of withdrawal signs following abrupt drug discontinuation, indicating that lemborexant does not induce physical dependence. In the drug discrimination study, lemborexant at doses up to 1000 mg/kg administered orally did not cross-generalize to the zolpidem training stimulus, although another DORA included in the same experiment, suvorexant, showed partial generalization with zolpidem. In rhesus monkeys, lemborexant treatment did not induce any gross behavioral changes, and there was no increase in self-administration rates compared with control, indicative of a lack of reinforcing effects of lemborexant. Collectively, these nonclinical studies support the position that lemborexant, which has been placed in Schedule IV by the United States Drug Enforcement Administration, has a low risk of abuse in humans.
雷美替胺是一种双重食欲素受体拮抗剂（DORA），已在多个国家获得批准，包括美国、日本、加拿大和澳大利亚，用于治疗成年人失眠症。与具有镇静作用的中枢神经系统活性的新化合物的上市批准要求一样，按照监管指南评估了雷美替胺的滥用潜力，其中包括三项非临床研究。这些评估包括在大鼠中进行的身体依赖性和药物辨别研究，以及在恒河猴中进行的自我给药研究。突然停止用药后没有戒断迹象，表明雷美替胺不会引起身体依赖性。在药物辨别研究中，口服给予高达 1000 mg/kg 的雷美替胺没有与唑吡坦的训练刺激交叉泛化，尽管在同一个实验中包含的另一种 DORA，苏沃雷生，与唑吡坦表现出部分泛化。在恒河猴中，雷美替胺治疗没有引起任何明显的行为变化，与对照相比，自我给药率没有增加，表明雷美替胺没有强化作用。总的来说，这些非临床研究支持雷美替胺（美国缉毒局将其列为附表 IV 药物）在人类中滥用风险低的观点。
