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Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes

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Summary

Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity profile has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice. Methods Blood samples at steady state were obtained during Cycle 1 from patients treated with regorafenib. Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatography–tandem mass spectrometry. The efficacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure–response relationships were assessed. Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was significantly longer in patients achieving total trough concentrations (Ctrough) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the first 2 cycles was significantly higher in patients with summed Ctrough levels ≥4.3 µg/mL than in others (p = 0.0003). Conclusions Dose titration of regorafenib to achieve drug-related Ctrough levels between 2.9 and 4.3 µg/mL in Cycle 1 may improve efficacy and safety, warranting further investigation in a larger patient population.

Clinical trial registry: Not applicable.

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Data availability

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.

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Acknowledgements

We thank all patients and medical staff who contributed to this study.

Funding

This work was supported in part by a grant from the Japan Society for the Promotion of Science (JSPS) KAKENHI (No. 16K08902) and a grant from the Foundation for Promotion of Cancer Research.

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Authors and Affiliations

  1. Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical University, Asahikawa, Japan

    Masahide Fukudo

  2. Department of Pharmacy, Sapporo Medical University Hospital, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan

    Masahide Fukudo

  3. Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan

    Keiko Asai, Chikayoshi Tani & Masashi Miyamoto

  4. Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan

    Katsuyoshi Ando & Nobuhiro Ueno

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  1. Masahide Fukudo
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  4. Masashi Miyamoto
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Contributions

Study concept and design: M.F.; acquisition, analysis, or interpretation of data: all authors; drafting of the manuscript: M.F.; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: M.F.; acquisition of funding: M.F.; administrative, technical, or material support: K.A., C.T., M.M., K.A., and N.U; supervision: M.F.

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Correspondence to Masahide Fukudo.

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No authors have any conflicts of interest to declare.

Informed consent

Written informed consent was obtained from each patient prior to enrollment.

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The protocol of this study was approved by the institutional ethics committee of Asahikawa Medical University (#15018). The study was performed in accordance with the Declaration of Helsinki and its amendments.All patients provided written informed consent to participate in the study.

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All authors approved the final version of the manuscript.

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Fukudo, M., Asai, K., Tani, C. et al. Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes. Invest New Drugs 39, 1422–1431 (2021). https://doi.org/10.1007/s10637-021-01115-4

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  • DOI: https://doi.org/10.1007/s10637-021-01115-4

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