Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
AMED-CREST, Agency for Medical Research and Development (AMED), Tokyo, 102-0004, Japan.
Med Oncol. 2018 Mar 9;35(4):51. doi: 10.1007/s12032-018-1113-8.
Axitinib is a potent second-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC). Axitinib pharmacokinetics and its relation with genetic polymorphisms were evaluated to predict the adverse events (AEs) and efficacy of axitinib. We analyzed 46 patients with mRCC who were treated with axitinib. The plasma axitinib level was measured at 0, 2, 4, 8, and 12 h after administration (C, C, C, C, and C; ng/mL) on day 7 of the treatment. Genetic polymorphisms related to axitinib pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed. Axitinib C and AUC in patients with UGT1A1 poor metabolisers (*6/*6, *6/*28, and *28/*28; n = 10) were significantly higher than those in patients with UGT1A1 extensive metabolisers (*1/*1, *1/*6,*1/*28, and *27/*28; n = 36) (23.6 vs. 7.8 ng/mL, p = 0.030, and 441.3 vs. 217.1 ng h/mL, p = 0.007). The cutoff levels of C to predict ≥ G2 hypothyroidism and ≥ G2 anorexia were 6.6 and 7.1 ng/mL, respectively (p = 0.005 and p = 0.035). The overall survival (OS) in patients with C > 5 ng/mL was significantly better than that in patients with C < 5 ng/mL (p = 0.022). Genetic polymorphisms in UGT1A1 were significantly associated with the plasma axitinib level. The plasma axitinib level was significantly associated with the frequency of AEs and OS in patients with mRCC. No direct relationship was observed between UGT1A1 genotypes and the frequency of AEs or OS.
阿昔替尼是一种有效的转移性肾细胞癌（mRCC）二线分子靶向药物。评估阿昔替尼的药代动力学及其与遗传多态性的关系，以预测阿昔替尼的不良反应（AE）和疗效。我们分析了 46 例接受阿昔替尼治疗的 mRCC 患者。在治疗第 7 天，在给药后 0、2、4、8 和 12 小时（C、C、C、C 和 C；ng/mL）测量血浆阿昔替尼水平。分析了与阿昔替尼药代动力学相关的遗传多态性，包括 SLCO1B1、SLCO1B3、SLCO2B1、ABCB1、ABCG2、CYP2C19、CYP3A5 和 UGT1A1。UGT1A1 弱代谢者（*6/*6、*6/*28 和 *28/*28；n=10）的阿昔替尼 C 和 AUC 明显高于 UGT1A1 广泛代谢者（*1/*1、*1/*6、*1/*28 和 *27/*28；n=36）（23.6 与 7.8 ng/mL，p=0.030 和 441.3 与 217.1 ng h/mL，p=0.007）。C 预测≥G2 甲状腺功能减退和≥G2 厌食的截断值分别为 6.6 和 7.1 ng/mL（p=0.005 和 p=0.035）。C>5 ng/mL 患者的总生存期（OS）明显优于 C<5 ng/mL 患者（p=0.022）。UGT1A1 中的遗传多态性与血浆阿昔替尼水平显著相关。血浆阿昔替尼水平与 mRCC 患者 AE 发生频率和 OS 显著相关。UGT1A1 基因型与 AE 发生频率或 OS 之间无直接关系。
