Abstract：
To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities.
METHODS: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed.
RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01).
CONCLUSIONS: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG.
CONCLUSIONS: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.
METHODS: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed.
RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01).
CONCLUSIONS: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG.
CONCLUSIONS: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.
摘要：
目的：探讨药物暴露和宿主种系遗传因素对阿帕替尼（APA）相关毒性的预测价值。
方法：在这项前瞻性研究中，血浆APA浓度定量使用液相色谱-串联质谱，对126例接受每日250mgAPA治疗的晚期实体瘤患者的57种系突变进行基因分型，血管内皮生长因子受体II抑制剂。药物暴露之间的相关性，遗传因素,并对其毒性进行了分析。
结果：非小细胞肺癌（NSCLC）更容易发生APA相关毒性，APA及其主要代谢产物M1-1的血浆浓度与高级别不良事件（AEs）（P＜0.01；M1-1：P＜0.01）和高级别抗血管生成毒性（APA：P=0.034；P＜0.05）有关，包括高血压,蛋白尿和手足综合征，在NSCLC亚组中。此外,CYP2C9rs34532201TT携带者倾向于有较高水平的APA(P＜0.001)和M1-1(P＜0.01),而CYP2C9rs1936968GG携带者倾向于有较高水平的M1-1(P＜0.01)。
结论：血浆APA和M1-1暴露能够预测NSCLC患者的严重AE。CYP2C9rs34532201TT和rs1936968GG的NSCLC患者可能需要考虑剂量优化和药物暴露监测。意义声明阿帕替尼是一种用于治疗多种癌症的抗VEGFR2抑制剂。虽然有实质性的回应，阿帕替尼引起的毒性一直是值得临床监测的关键问题.关于药物暴露和遗传因素在阿帕替尼诱导的毒性中的作用的数据很少。我们的研究表明在NSCLC中存在明显的药物暴露关系，而不是其他肿瘤，并提供了药物暴露水平和单核苷酸多态性作为阿帕替尼诱导的严重毒性的预测生物标志物的宝贵证据。
方法：在这项前瞻性研究中，血浆APA浓度定量使用液相色谱-串联质谱，对126例接受每日250mgAPA治疗的晚期实体瘤患者的57种系突变进行基因分型，血管内皮生长因子受体II抑制剂。药物暴露之间的相关性，遗传因素,并对其毒性进行了分析。
结果：非小细胞肺癌（NSCLC）更容易发生APA相关毒性，APA及其主要代谢产物M1-1的血浆浓度与高级别不良事件（AEs）（P＜0.01；M1-1：P＜0.01）和高级别抗血管生成毒性（APA：P=0.034；P＜0.05）有关，包括高血压,蛋白尿和手足综合征，在NSCLC亚组中。此外,CYP2C9rs34532201TT携带者倾向于有较高水平的APA(P＜0.001)和M1-1(P＜0.01),而CYP2C9rs1936968GG携带者倾向于有较高水平的M1-1(P＜0.01)。
结论：血浆APA和M1-1暴露能够预测NSCLC患者的严重AE。CYP2C9rs34532201TT和rs1936968GG的NSCLC患者可能需要考虑剂量优化和药物暴露监测。意义声明阿帕替尼是一种用于治疗多种癌症的抗VEGFR2抑制剂。虽然有实质性的回应，阿帕替尼引起的毒性一直是值得临床监测的关键问题.关于药物暴露和遗传因素在阿帕替尼诱导的毒性中的作用的数据很少。我们的研究表明在NSCLC中存在明显的药物暴露关系，而不是其他肿瘤，并提供了药物暴露水平和单核苷酸多态性作为阿帕替尼诱导的严重毒性的预测生物标志物的宝贵证据。
