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Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma

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Summary

Purpose Axitinib is an orally active multikinase inhibitor currently used to treat patients with metastatic renal cell carcinoma (RCC). This study examined the pharmacokinetics of axitinib and the relationship between peak drug concentration (Cmax) and clinical outcomes in real-world practice. Methods Twenty patients with metastatic RCC treated with axitinib monotherapy were enrolled. Post-dose (1–4 h) blood samples were obtained, and axitinib Cmax in plasma was measured by liquid chromatography–tandem mass spectrometry. Efficacy endpoints were best overall response (per RECIST 1.1) and progression-free survival (PFS). The safety endpoint was the cumulative incidence of dose-limiting toxicities (DLTs). Results Large inter- and intra-individual variability in dose-adjusted Cmax was observed (0.02–11.2 ng/mL/mg). Axitinib absorption was significantly influenced by glucuronidation activity (P = 0.040). Cmax at steady state was significantly higher in responders than in non-responders (P = 0.013). The optimal Cmax cutoff to predict a clinical response was 12.4 ng/mL. The median PFS was significantly longer in patients who achieved an average steady state Cmax above the threshold than in those who did not (799 vs. 336 days; P = 0.047). The cumulative incidence of DLTs was significantly higher in patients with Cmax ≥ 40.2 ng/mL than in other patients (sub-hazard ratio, 4.13; 95% confidence interval, 1.27–13.5; P = 0.019). Conclusions The potential therapeutic window of axitinib Cmax in metastatic RCC was estimated at 12.4–40.2 ng/mL. Pharmacokinetically guided dose titration using therapeutic drug monitoring may improve the efficacy and safety of axitinib, warranting further investigation in a larger patient population.

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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. 16 K08902) 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 & Yoshikazu Tasaki

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

    Masahide Fukudo

  3. Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan

    Gaku Tamaki, Makoto Azumi & Hidehiro Kakizaki

  4. Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa, Japan

    Seiji Matsumoto

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  1. Masahide Fukudo
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Contributions

Study concept and design: Masahide Fukudo, Seiji Matsumoto; Acquisition, analysis, or interpretation of data: all authors; Drafting of the manuscript: Masahide Fukudo; Critical revision of the manuscript for important intellectual content: all authors; Statistical analysis: Masahide Fukudo; Obtained funding: Masahide Fukudo; Administrative, technical, or material support: Gaku Tamaki, Makoto Azumi, Hidehiro Kakizaki; Supervision: Masahide Fukudo.

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Correspondence to Masahide Fukudo.

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Ethical approval

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.

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All patients provided written informed consent to participate in the study.

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Fukudo, M., Tamaki, G., Azumi, M. et al. Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma. Invest New Drugs 39, 595–604 (2021). https://doi.org/10.1007/s10637-020-01023-z

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