Heng Jianfu, Tang Qi, Chen Xue, Bao Jingjing, Deng Jun, Chen Yong, Zhao Jiao, Zhu Songlin, Liu Xiaobao, Yang Feng, Jiang Yun, Yang Nong, Li Kunyan
Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China.
Department of Early Clinical Trail Center, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China.
Eur J Pharm Sci. 2021 Jul 1;162:105815. doi: 10.1016/j.ejps.2021.105815. Epub 2021 Mar 23.
Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor for the treatment of lung cancer patients with T790M-resistant mutations. It is metabolized mainly by the CYP3A4 enzyme. At the same time, it has the potential to induce CYP3A4. In this study, we aimed to estimate the effect of itraconazole (a strong inhibitor of CYP3A4) on the pharmacokinetics of alflutinib. For this aim, a single-center, open-label, single-sequence, two-period trial was designed. The pharmacokinetic parameters of AST2818 and its active metabolite AST5902 were established from blood concentration measurements, and adverse events (AEs) of two periods of treatment were documented. For AST2818, the C, AUC, and AUC in period II (coadministration of itraconazole) increased by 6.5 ng/mL, 1263.0 hng/mL, and 1067.0 hng/mL, respectively. And the corresponding 90% CIs were 1.23 (1.14-1.32), 2.41 (2.29-2.54), and 2.22 (2.11-2.34), respectively. The C, AUC, and AUC of AST5902 in period II decreased by 4.849 ng/mL, 415.60 hng/mL, and 391.4 hng/mL, respectively. Moreover, the corresponding 90% CIs were 0.09 (0.08-0.10), 0.18 (0.17-0.19), and 0.14 (0.13-0.15), respectively. Nonetheless, in period II, plasma concentrations of total active components (AST2818 and AST5902) changed marginally. The AUC of total active components increased 60%, and the corresponding C increased 8%. Possible treatment-related AEs assessed by investigators were fewer in period II (23.3% vs 36.7%). In conclusion, the total exposure of AST2818 and active metabolite AST5902 increased following the coadministration of itraconazole, but it was still safe and well-tolerated.
阿弗替尼（AST2818）是一种新开发的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，用于治疗具有T790M耐药突变的肺癌患者。它主要通过细胞色素P450 3A4（CYP3A4）酶代谢。同时，它有诱导CYP3A4的潜力。在本研究中，我们旨在评估伊曲康唑（一种强效CYP3A4抑制剂）对阿弗替尼药代动力学的影响。为此，设计了一项单中心、开放标签、单序列、两阶段试验。通过血药浓度测定确定AST2818及其活性代谢产物AST5902的药代动力学参数，并记录两个治疗阶段的不良事件（AE）。对于AST2818而言，第二阶段（伊曲康唑合用）的Cmax、AUCτ和AUC0-∞分别增加了6.5 ng/mL、1263.0 hng/mL和1067.0 hng/mL。相应的90%置信区间分别为1.23（1.14 - 1.32）、2.41（2.29 - 2.54）和2.22（2.11 - 2.34）。第二阶段AST5902的Cmax、AUCτ和AUC0-∞分别降低了4.849 ng/mL、415.60 hng/mL和391.4 hng/mL。此外，相应的90%置信区间分别为0.09（0.08 - 0.10）、0.18（0.17 - 0.19）和0.14（0.13 - 0.15）。尽管如此，在第二阶段，总活性成分（AST2818和AST5902）的血浆浓度变化不大。总活性成分的AUC增加了60%，相应的Cmax增加了8%。研究者评估的可能与治疗相关的AE在第二阶段较少（23.3%对36.7%）。总之，伊曲康唑合用后AST2818及其活性代谢产物AST5902的总暴露量增加，但仍安全且耐受性良好。
