Physiologically-based pharmacokinetic modeling to predict drug interactions of lemborexant with CYP3A inhibitors

Abstract

Lemborexant, a recently approved dual orexin receptor antagonist for treatment of adults with insomnia, is eliminated primarily by cytochrome P450 (CYP)3A metabolism. The recommended dose of lemborexant is 5 mg once per night, with a maximum recommended dose of 10 mg once daily. A physiologically-based pharmacokinetic (PBPK) model for lemborexant was developed and applied to integrate data obtained from in vivo drug-drug interaction (DDI) assessments, and to further explore lemborexant interaction with CYP3A inhibitors and inducers. The model predictions were in good agreement with observed pharmacokinetic data and with DDI results from clinical studies with CYP3A inhibitors, itraconazole and fluconazole. The model further predicted that DDI effects of weak CYP3A inhibitors (fluoxetine and ranitidine) are weak, and effects of moderate inhibitors (erythromycin and verapamil) are moderate. Based on the PBPK simulations and clinical efficacy and safety data, the maximum daily recommended lemborexant dose when administered with weak CYP3A inhibitors is 5 mg; co-administration of moderate and strong inhibitors should be avoided except in countries where 2.5 mg has been approved.

FIGURE 1

Overall steps of model development/verification and application to DDI predictions. DDI, drug–drug interaction; PBPK, physiologically‐based pharmacokinetic; PK, pharmacokinetics

FIGURE 2

Predicted and observed plasma concentration–time profiles of lemborexant in healthy volunteers under fasted conditions. IR, immediate release

FIGURE 3

Predicted and observed plasma concentration–time profiles of lemborexant in healthy volunteers after co‐administration with CYP3A4 inducers and inhibitors