Physiologically Based Pharmacokinetic Modeling of Lemborexant: Exploration of Doses for Populations with Hepatic Impairment

Lemborexant, a dual orexin receptor antagonist, is suitable for the long-term treatment of insomnia. It is primarily metabolized in the liver. The aim was to develop physiologically based pharmacokinetic (PBPK) models of lemborexant to provide dosing regimens for populations with hepatic impairment. The PBPK models of lemborexant were developed and validated using PK-Sim for healthy populations and populations with mild, moderate hepatic impairment, respectively. Then, the effect of severe hepatic impairment on lemborexant pharmacokinetics was investigated to determine dosing regimens. The developed model successfully described the pharmacokinetics of lemborexant in healthy and hepatic impairment populations. Mean plasma concentrations of lemborexant were higher in populations with hepatic impairment compared to those with normal hepatic function. The area under the plasma concentration-time curve at steady state (AUC_ss,24h) values in populations with mild, moderate, and severe hepatic impairment were 1.54-, 2.18-, and 2.08-fold higher, respectively, compared to those with normal hepatic function. Based on the changes in exposure, it is recommended that the maximum dose for populations with severe hepatic impairment should be limited to 5 mg once daily, which is similar to moderate hepatic impairment. The PBPK model can be used as a tool for dose adjustments in populations with hepatic impairment.