Disposition and metabolism of [¹⁴C]lemborexant, a novel dual orexin receptor antagonist, in rats and monkeys

Abstract

1. The disposition and metabolism of lemborexant, a novel dual orexin receptor antagonist currently under development as a therapeutic agent for insomnia disorder, were evaluated after a single oral administration of [¹⁴C]lemborexant in Sprague-Dawley rats (10 mg/kg) and cynomolgus monkeys (3 mg/kg).

2. In both species, [¹⁴C]lemborexant was rapidly absorbed: radioactivity concentration in blood peaked at 0.83–1.8 h, and decreased with elimination half-life of 110 h. The radioactivity administered was excreted primarily into faeces, with relatively little excreted into urine.

3. Lemborexant was not detected in bile, urine or faeces, indicating that lemborexant administered orally was completely absorbed from the gastrointestinal tract and that the main elimination pathway was metabolism in both species.

4. In rats, lemborexant was found to be minor in plasma (≤5.2% of total radioactivity), and M9 (hydroxylated form) was the major circulating metabolite. In monkeys, the major circulating components were lemborexant, M4 (N-oxide metabolite), M13 (di-oxidised form), M14 (di-oxidised form) and M16 (glucuronide of mono-oxidised form).

5. In both species, lemborexant was metabolised to various metabolites by multiple pathways, the primary of which was oxidation of the dimethylpyrimidine or fluorophenyl moiety.

Keywords:

• Lemborexant
• metabolism
• disposition
• orexin
• hypocretin

Acknowledgements

The authors thank Carsten T. Beuckmann of Eisai Co., Ltd. and Margaret Moline of Eisai Inc. for their critical review of and insightful comments on the manuscript. The authors also thank Nobuaki Shirai of Nemoto Science Co., Ltd. and Kohei Nozawa of Sekisui Medical Co., Ltd. for performing in vivo experiments and metabolite analyses, respectively.

Disclosure statement

The authors report no conflict of interest. All authors are employees of Eisai Co., Ltd.