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Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers

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Abstract

Purpose

The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer.

Methods

The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5.

Results

We analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035).

Conclusion

This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.

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Acknowledgements

First, we thank all the patients who participated in this study. Furthermore, we would like to thank Chiyo Imamura for assistance during the clinical study.

Funding

This work was supported by Japan Research Foundation for Clinical Pharmacology (to Dr. Wakatsuki).

Author information

Authors and Affiliations

  1. Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Kazuo Kobayashi, Takeshi Aoyama, Yasuhiro Nakano, Kazuyoshi Kawakami, Koki Hashimoto, Wataru Suzuki, Takashi Yokokawa, Yuichi Minowa, Tomoko Hiraoka & Toshihiro Hama

  2. Division of Pharmacokinetics and Pharmacodynamics, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Kazuo Kobayashi, Erika Sugiyama, Masataka Tajima, Hiyori Kidokoro & Hitoshi Sato

  3. Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Eiji Shinozaki, Takeru Wakatsuki, Mitsukuni Suenaga, Takashi Ichimura, Mariko Ogura, Keisho Chin, Izuma Nakayama, Akira Ooki, Daisuke Takahari & Kensei Yamaguchi

  4. Department of Specialized Surgeries, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Mitsukuni Suenaga

  5. Division of Applied Pharmaceutical Education and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Kenichi Suzuki

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  1. Kazuo Kobayashi
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  2. Erika Sugiyama
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  3. Eiji Shinozaki
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  4. Takeru Wakatsuki
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  14. Keisho Chin
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Corresponding author

Correspondence to Kazuo Kobayashi.

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Conflict of interest

K. Yamaguchi has received speaking honorariums from Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Serono, Takeda Pharmaceutical, Yakult, Bayer, Ono Pharmaceutical, Eli Lilly, Sanofi and Bristol-Myers Squibb, and has received research grants from MSD, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead Sciences, and Yakult. Also, he has served in a consulting or advisory role for Bristol-Myers Squibb. The other authors declare that they have no conflicts of interest.

Ethical approval

This study was conducted in accordance with the World Medical Association Declaration of Helsinki and independently reviewed and approved by the Clinical Research Ethics Review Committee of the hospital (approval no. 2017-1205). All patients provided written informed consent for the use of their blood samples and medical information for research purposes. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN no. 000032725).

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Kobayashi, K., Sugiyama, E., Shinozaki, E. et al. Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers. Cancer Chemother Pharmacol 87, 767–777 (2021). https://doi.org/10.1007/s00280-021-04237-x

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