Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant

Abstract

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.