Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Fondazione IRCCS-Istituto Nazionale Dei Tumori, Milano, Italy.
Cancer Chemother Pharmacol. 2021 Apr;87(4):475-486. doi: 10.1007/s00280-020-04180-3. Epub 2021 Jan 4.
Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively.
This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily.
Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC.
Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.
塞瑞替尼是一种 ALK 受体酪氨酸激酶抑制剂，已被批准用于治疗 ALK+转移性非小细胞肺癌（NSCLC）的成年患者的一线和二线治疗。本研究旨在研究塞瑞替尼与咪达唑仑和华法林合用时，作为 CYP3A 和 CYP2C9 活性的探针底物的药物相互作用（DDI）潜力。
这是一项在 33 名 ALK+NSCLC 或其他晚期肿瘤的成年患者中进行的 I 期、多中心、开放标签、单序列、交叉 DDI 研究。单次给予咪达唑仑和华法林的鸡尾酒，同时给予和不给予塞瑞替尼。主要目的是评估咪达唑仑和华法林的药代动力学。次要目的包括塞瑞替尼 750mg 每日一次的药代动力学、安全性、耐受性、总缓解率（ORR）和缓解持续时间（DOR）。
塞瑞替尼抑制了 CYP3A 介导的咪达唑仑代谢，导致 AUC（几何均数比[90%置信区间]）显著增加 5.4 倍（4.6，6.3）。塞瑞替尼还导致 S-华法林的 AUC 增加 54%（36%，75%）。本研究中塞瑞替尼的药代动力学和安全性特征与之前的报告一致，没有报告新的安全性信号。在 19 名 NSCLC 患者中，疗效（ORR：42.1%和 DCR：63.2%）与之前报道的预处理的 ALK+NSCLC 患者的研究相似。
塞瑞替尼是一种强 CYP3A 抑制剂和弱 CYP2C9 抑制剂。这些发现应反映在塞瑞替尼的说明书中，以指导与可能因塞瑞替尼而改变其药代动力学的药物合用的临床建议。
