Wang Dongxu, Wang Shuanghu, Wu Hualan, Geng Peiwu, An Yang, Zhou Xiaoyue, Du Minghui, Li Yuwei, Chong Jia, Li Yingying, Wang Fang, Lu Zebei, Wang Yu, Yang Jiefu, Li Chuanbao, Dai Dapeng, Chen Hao
Department of Cardiovascular, Beijing Hospital, National Centre of Gerontology, Beijing, China.
Arrhythmia Center, Fuwai Hospital, Chinese Academy of Medical Sciences, National Center for Cardiovascular Diseases, Beijing, China.
PLoS One. 2025 Jun 3;20(6):e0322303. doi: 10.1371/journal.pone.0322303. eCollection 2025.
Tyrosine kinase inhibitor (TKI) and rivaroxaban co-administration is common for patients with cancer and venous thromboembolism. However, the drug-drug interactions (DDIs) between epidermal growth factor receptor (EGFR) TKIs and rivaroxaban remain uncertain.
DDIs were investigated in vitro and in vivo. In vitro experiments were conducted using rat liver microsomes, and rivaroxaban metabolites were tested to identify the two TKIs that exhibit the most significant DDIs. The type of inhibition was investigated using Lineweaver-Burk plots. For in vivo experiments, eighteen rats were randomly divided into three groups and pretreated with CMC-Na together with avitinib or gefitinib, or with CMC-Na alone for 7 days. On day 8, rivaroxaban was orally administered to each group. Blood samples were collected at various time points, and plasma rivaroxaban was quantified. Molecular docking was performed to explore the mechanism of DDIs.
Avitinib and gefitinib showed the most potent inhibitory effects among multiple EGFR TKIs and inhibited rivaroxaban metabolism in a mixed model of noncompetitive and uncompetitive inhibition. The area under the drug-time curve and maximum plasma concentration of rivaroxaban were significantly higher following avitinib and gefitinib pretreatment, while the apparent volume of distribution and clearance rates were significantly lower. Our molecular docking analysis revealed that these two drugs may inhibit rivaroxaban metabolism by overlapping with its binding site on CYP3A4 and CYP2D6.
These findings confirm the presence of DDIs between EGFR TKIs and rivaroxaban. Avitinib and gefitinib significantly inhibit rivaroxaban metabolism, and their co-administration may aggravate the risk of bleeding.
酪氨酸激酶抑制剂（TKI）与利伐沙班联合给药在癌症合并静脉血栓栓塞患者中很常见。然而，表皮生长因子受体（EGFR）TKI与利伐沙班之间的药物相互作用（DDI）仍不明确。
在体外和体内研究DDI。使用大鼠肝微粒体进行体外实验，并测试利伐沙班代谢物以确定表现出最显著DDI的两种TKI。使用Lineweaver-Burk图研究抑制类型。对于体内实验，将18只大鼠随机分为三组，分别用羧甲基纤维素钠（CMC-Na）联合阿维替尼或吉非替尼预处理，或仅用CMC-Na预处理7天。在第8天，每组口服利伐沙班。在不同时间点采集血样，并对血浆利伐沙班进行定量。进行分子对接以探索DDI的机制。
在多种EGFR TKI中，阿维替尼和吉非替尼显示出最有效的抑制作用，并在非竞争性和非竞争性抑制的混合模型中抑制利伐沙班代谢。阿维替尼和吉非替尼预处理后，利伐沙班的药时曲线下面积和最大血浆浓度显著升高，而表观分布容积和清除率显著降低。我们的分子对接分析表明，这两种药物可能通过与CYP3A4和CYP2D6上的结合位点重叠来抑制利伐沙班代谢。
这些发现证实了EGFR TKI与利伐沙班之间存在DDI。阿维替尼和吉非替尼显著抑制利伐沙班代谢，它们联合给药可能会增加出血风险。
