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

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Abstract

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.

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Acknowledgements

The authors thank Yoko Mitobe, Yukiko Sugiyama, and Ikuka Izumida for their contribution of clinical sample collections and preparations. This work was supported by the Grant Numbers 25293332, 16H02679, and 23590168 from the Japanese Society for the Promotion of Science and AMED-CREST, Japan Agency for Medical Research and Development (AMED).

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Authors and Affiliations

  1. Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Ryoma Igarashi, Takamitsu Inoue, Kazuyuki Numakura, Mitsuru Saito, Shintaro Narita & Tomonori Habuchi

  2. AMED-CREST, Agency for Medical Research and Development (AMED), Tokyo, 102-0004, Japan

    Takamitsu Inoue, Shintaro Narita & Tomonori Habuchi

  3. Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan

    Nobuhiro Fujiyama & Shigeru Satoh

  4. Department of Urology, Faculty of Medicine, Yamagata University, Yamagata, Japan

    Norihiko Tsuchiya

  5. Department of Pharmacy, Akita University Hospital, Akita, Japan

    Nobuhiro Fujiyama, Hideaki Kagaya, Takenori Niioka & Masatomo Miura

  6. Department of Pharmacy, Hirosaki University Hospital, Aomori, Japan

    Takenori Niioka

Authors
  1. Ryoma Igarashi
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  2. Takamitsu Inoue
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  12. Tomonori Habuchi
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Correspondence to Takamitsu Inoue.

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Supplementary Figure 1

Progression-free survival (PFS) based on the plasma axitinib level. A: PFS in patients with C0 ≥5 ng/mL (n = 31) was not significantly better than that in patients with C0 < 5 ng/mL (n = 15). B: PFS in patients with AUC0–12 ≥300 ng·h/mL (n = 28) was not significantly better than that in patients with AUC0–12 < 300 ng·h/mL (n = 18). C: PFS in TKI-naïve patients with C0 ≥5 ng/mL (n = 22) was not significantly better than that in patients with C0 < 5 ng/mL (n = 11). B: PFS in TKI-naïve patients with AUC0–12 ≥300 ng·h/mL (n = 20) was not significantly better than that in patients with AUC0–12 < 300 ng·h/mL (n = 13)

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Igarashi, R., Inoue, T., Fujiyama, N. et al. Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma. Med Oncol 35, 51 (2018). https://doi.org/10.1007/s12032-018-1113-8

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  • DOI: https://doi.org/10.1007/s12032-018-1113-8

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