論文

査読有り 国際誌
2018年3月9日

Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma.

Medical oncology (Northwood, London, England)
  • Ryoma Igarashi
  • ,
  • Takamitsu Inoue
  • ,
  • Nobuhiro Fujiyama
  • ,
  • Norihiko Tsuchiya
  • ,
  • Kazuyuki Numakura
  • ,
  • Hideaki Kagaya
  • ,
  • Mitsuru Saito
  • ,
  • Shintaro Narita
  • ,
  • Shigeru Satoh
  • ,
  • Takenori Niioka
  • ,
  • Masatomo Miura
  • ,
  • Tomonori Habuchi

35
4
開始ページ
51
終了ページ
51
記述言語
英語
掲載種別
研究論文(学術雑誌)
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 (C0, C2, C4, C8, and C12; 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 C0 and AUC0-12 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 C0 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 C0 > 5 ng/mL was significantly better than that in patients with C0 < 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.

リンク情報
DOI
https://doi.org/10.1007/s12032-018-1113-8
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29524031

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