Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer
Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer
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CYP3A4/5和ABC转运蛋白多态性对日本非小细胞肺癌患者奥希替尼血药浓度的影响
DOI：
10.1007/s10637-022-01304-9
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发表时间：
2022
影响因子：
3.4
通讯作者：
Miura Masatomo
中科院分区：
文献类型：
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作者：
Yokota Hayato;Sato Kazuhiro;Sakamoto Sho;Okuda Yuji;Fukuda Natsuki;Asano Mariko;Takeda Masahide;Nakayama Katsutoshi;Miura Masatomo
在23例非小细胞肺癌患者中，研究了CYP 3A 4（20230 G> A）、CYP 3A 5（6986 A> G）、ABCB 1（1236 C> T，2677 G> T/A，3435 C> T）、ABCG 2（421 C> A）和ABCC 2（-24 C> T）基因多态性对奥希替尼浓度-时间曲线下面积（AUC）的影响。在治疗开始后第15天稳态奥希替尼给药前和给药后1、2、4、6、8、12和24 h采集血样。奥希替尼AUC 0 - 24与年龄（P= 0.038）、血清白蛋白（P= 0.002）和血清肌酐（P= 0.012）显著相关。此外，沃诺拉赞、组胺2受体拮抗剂或埃索美拉唑给药组和无抑酸剂给药组之间奥希替尼的AUC 0 - 24存在显著差异（P= 0.021）。相比之下，在CYP 3A 4/5或ABC转运蛋白基因型之间，奥希替尼的AUC 0 - 24无显著差异。此外，腹泻、皮疹或肝毒性患者与无这些疾病的患者之间奥希替尼的AUC 0 - 24无显著差异。多变量分析中，仅血清白蛋白值是预测奥希替尼AUC 0 - 24的独立因素。在奥希替尼治疗前分析CYP 3A 4/5和ABC转运蛋白多态性可能无法预测奥希替尼的疗效或副作用。较低的血清白蛋白值与奥希替尼的AUC 0 - 24增加相关;然而，需要进一步研究来评估导致奥希替尼药代动力学个体间变异性的因素。
The effects of polymorphisms inCYP3A4(20230G > A),CYP3A5(6986A > G),ABCB1(1236C > T, 2677G > T/A, 3435C > T),ABCG2(421C > A), andABCC2(-24C > T) on the area under the concentration–time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24 h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24was significantly correlated with age (P= 0.038), serum albumin (P= 0.002), and serum creatinine (P= 0.012). Additionally, there were significant differences in the AUC0-24of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P= 0.021). By contrast, there were no significant differences in the AUC0-24of osimertinib between genotypes ofCYP3A4/5orABCtransporters. Furthermore, there were no significant differences in the AUC0-24of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24of osimertinib. Analysis ofCYP3A4/5andABCtransporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics.