DataSheet1_Studies on the inhibitory effect of isavuconazole on flumatinib metabolism in vitro and in vivo.pdf

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66 μM in human liver microsomes (HLM), while 0.62 μM in rat liver microsomes (RLM) and 2.90 μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0−t), AUC(0−∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.

作为慢性髓性白血病（chronic myelogenous leukemia, CML）的获批治疗药物，氟马替尼（flumatinib）是一种新型口服酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），相较于伊马替尼（imatinib），其对BCR-ABL1激酶具有更优的效力与选择性。诸多慢性髓性白血病患者会罹患曲霉菌感染，此时可能需要使用艾沙康唑（isavuconazole）——一种CYP3A4抑制剂。然而，目前尚无关于二者体外及体内相互作用的相关研究。本研究采用稳定的超高效液相色谱串联质谱法（ultra-performance liquid chromatography tandem mass spectrometry, UPLC-MS/MS），快速测定了氟马替尼及其主要代谢物M1的浓度。在人肝微粒体（human liver microsomes, HLM）中，其半数抑制浓度（half-maximal inhibitory concentration, IC50）为6.66 μM；在大鼠肝微粒体（rat liver microsomes, RLM）中为0.62 μM；在重组人CYP3A4（recombinant human CYP3A4, rCYP3A4）中则为2.90 μM。进一步研究表明，艾沙康唑对人肝微粒体、大鼠肝微粒体及重组人CYP3A4介导的氟马替尼代谢的抑制作用均为混合型抑制。此外，相较于伊曲康唑（itraconazole）、氟康唑（fluconazole）及伏立康唑（voriconazole），酮康唑（ketoconazole）、泊沙康唑（posaconazole）与艾沙康唑对人肝微粒体介导的氟马替尼代谢展现出更强的抑制活性。在大鼠药代动力学实验中，观察到艾沙康唑可显著改变氟马替尼的药代动力学参数，包括0-t时间段血药浓度-时间曲线下面积（AUC(0−t)）、0至无穷大血药浓度-时间曲线下总面积（AUC(0−∞)）、峰浓度（Cmax）及表观终末清除率/生物利用度（CLz/F），但对代谢物M1的代谢无明显影响。综合体外与体内实验结果，艾沙康唑可抑制氟马替尼的代谢，提示其可能升高氟马替尼的血浆药物浓度。因此，在临床应用中需格外关注氟马替尼与艾沙康唑之间的药物相互作用。