Eisai Inc., Woodcliff Lake, New Jersey, USA.
Eisai Co., Ltd, Tokyo, Japan.
Clin Pharmacol Drug Dev. 2021 Jun;10(6):681-690. doi: 10.1002/cpdd.915. Epub 2021 Jan 17.
Lemborexant is approved for treating insomnia and is under investigation for treating irregular sleep-wake rhythm disorder. Based on in vitro drug-drug interaction (DDI) characteristics, phase 1, open-label DDI studies were conducted to evaluate lemborexant's cytochrome P450 3A (CYP3A) and CYP2B6 interaction potential. Interactions between lemborexant 10 mg and strong and moderate CYP3A inhibitors (itraconazole and fluconazole), a strong CYP3A inducer (rifampin), and CYP3A (midazolam) and CYP2B6 substrates (bupropion) were evaluated. Coadministration of lemborexant with itraconazole or fluconazole resulted in 1.4- to 1.6-fold and 3.7- to 4-fold increases in lemborexant maximum observed concentration (C ) and area under the concentration-time curve from zero time extrapolated to infinity (AUC ), respectively. Coadministration of lemborexant with rifampin resulted in >90% decreases in lemborexant C and AUC . Midazolam exposure was not affected. Coadministration of lemborexant with bupropion resulted in 49.9% and 45.5% decreases in S-bupropion C and AUC , respectively.Comparison of estimated exposures for patients in phase 3 trials who were/were not receiving concomitant weak CYP3A inhibitors substantiated the DDI pharmacokinetic findings. Lemborexant was generally well tolerated in the phase 1 studies. In summary, lemborexant does not affect the pharmacokinetics of CYP3A substrates and has potential to induce CYP2B6. Consistent with in vitro findings, moderate and strong CYP3A inhibitors and inducers affected the pharmacokinetics of lemborexant; hence, patients taking lemborexant 5 or 10 mg should avoid coadministration with moderate and strong CYP3A inhibitors and inducers.
雷美替胺已获批准用于治疗失眠症，目前正在研究其治疗睡眠-觉醒节律障碍的效果。根据体外药物相互作用（DDI）特征，开展了Ⅰ期、开放性 DDI 研究，以评估雷美替胺对细胞色素 P450 3A（CYP3A）和 CYP2B6 的相互作用潜力。评估了雷美替胺 10mg 与强 CYP3A 抑制剂（酮康唑和氟康唑）、强 CYP3A 诱导剂（利福平）以及 CYP3A（咪达唑仑）和 CYP2B6 底物（安非他酮）之间的相互作用。雷美替胺与酮康唑或氟康唑合用使雷美替胺最大观察浓度（C ）和从零时外推至无穷大的浓度-时间曲线下面积（AUC ）分别增加 1.4 至 1.6 倍和 3.7 至 4 倍。雷美替胺与利福平合用使雷美替胺 C 和 AUC 分别降低>90%。咪达唑仑暴露不受影响。雷美替胺与安非他酮合用使 S-安非他酮 C 和 AUC 分别降低 49.9%和 45.5%。比较了在接受或不接受弱 CYP3A 抑制剂联合治疗的Ⅲ期试验患者中的估计暴露量，这些结果证实了 DDI 药代动力学发现。雷美替胺在Ⅰ期研究中通常具有良好的耐受性。总之，雷美替胺不影响 CYP3A 底物的药代动力学，并有诱导 CYP2B6 的潜力。与体外研究结果一致，中效和强效 CYP3A 抑制剂和诱导剂影响雷美替胺的药代动力学；因此，服用雷美替胺 5 或 10mg 的患者应避免与中效和强效 CYP3A 抑制剂和诱导剂合用。
