Formerly of Eisai Inc, 155 Tice Blvd, Woodcliff Lake, NJ, 07677, USA.
Biostatistics, Oncology Business Group, Eisai Inc, Woodcliff Lake, NJ, USA.
Eur J Drug Metab Pharmacokinet. 2020 Jun;45(3):373-383. doi: 10.1007/s13318-020-00607-7.
Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib.
This multicenter, open-label, nonrandomized, phase 1 study involved patients with advanced cancer that progressed after treatment with approved therapies or for which no standard therapies were available.
Compared with baseline, coadministration of lenvatinib decreased the geometric mean ratio of the area under the concentration-time curve for midazolam on day 1 to 0.914 (90% confidence interval [CI] 0.850-0.983) but increased it on day 14 to 1.148 (90% CI 0.938-1.404). Coadministration of lenvatinib also decreased the geometric mean ratio of the maximum observed concentration for midazolam on day 1 to 0.862 (90% CI 0.753-0.988) but increased it on day 14 to 1.027 (90% CI 0.852-1.238). There was little change in the terminal elimination phase half-life of midazolam when administered with lenvatinib. The most common treatment-related adverse events were hypertension (20.0%), fatigue (16.7%), and diarrhea (10.0%).
Coadministration of lenvatinib had no clinically relevant effect on the pharmacokinetics of midazolam, a CYP3A4 substrate. The adverse events were consistent with the known safety profile of lenvatinib, and no new safety concerns were identified. CLINICALTRIALS.
NCT02686164.
仑伐替尼是一种多激酶抑制剂，它可以抑制酶的活性，但会诱导细胞色素 P450 3A4（CYP3A4）的基因表达，CYP3A4 是一种重要的药物代谢酶。我们使用咪达唑仑作为探针底物，评估仑伐替尼对晚期实体瘤患者 CYP3A4 的影响。主要目的是确定仑伐替尼对咪达唑仑的药代动力学影响，次要目的是评估仑伐替尼的安全性。
这是一项多中心、开放性、非随机、I 期研究，纳入了接受过批准治疗或无标准治疗的晚期癌症患者。
与基线相比，仑伐替尼联合用药使咪达唑仑第 1 天的浓度-时间曲线下面积的几何均数比值从 0.914（90%置信区间 [CI]：0.850-0.983）降低到第 14 天的 1.148（90%CI：0.938-1.404）。仑伐替尼联合用药还使咪达唑仑第 1 天的最大观察浓度的几何均数比值从 0.862（90%CI：0.753-0.988）降低到第 14 天的 1.027（90%CI：0.852-1.238）。仑伐替尼联合用药对咪达唑仑的终末消除相半衰期几乎没有影响。最常见的与治疗相关的不良事件是高血压（20.0%）、疲劳（16.7%）和腹泻（10.0%）。
仑伐替尼联合用药对咪达唑仑（CYP3A4 底物）的药代动力学无临床相关影响。不良事件与仑伐替尼已知的安全性特征一致，未发现新的安全性问题。临床试验.gov 标识符：NCT02686164。
