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Real-world pharmacokinetics and pharmacodynamics of everolimus in metastatic breast cancer

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Summary

Purpose This study investigated the relationship between the pharmacokinetics and pharmacodynamics of everolimus in patients with metastatic breast cancer (mBC) in real-world practice.Methods Twenty-two patients with mBC treated with everolimus plus exemestane were enrolled. Blood everolimus concentrations were measured at outpatient visits. The inhibition of the mammalian target of rapamycin (mTOR) activity in peripheral blood mononuclear cells (PBMCs) was examined. The efficacy and safety endpoints were progression-free survival (PFS) and the cumulative incidence of dose-limiting toxicities (DLTs), respectively. Results Blood samples were obtained from 19 consenting patients. Everolimus did not completely inhibit mTOR activity in PBMCs at therapeutic concentrations (~ 56 % maximal inhibition). The most common adverse event was stomatitis (any grade 77 %). The trough concentration (Ctrough) was significantly higher in patients experiencing DLTs than in those without any DLTs (P = 0.030). The optimal Ctrough cutoff predicting DLT development was 17.3 ng/mL. The cumulative incidence of DLTs was significantly higher in patients with Ctrough ≥17.3 ng/mL than in other patients (sub-hazard ratio 4.87, 95 % confidence interval [CI] 1.53–15.5; P = 0.007). Furthermore, the median PFS was numerically longer in patients who maintained a steady-state Ctrough below the threshold than in those who did not (327 days [95 % CI 103–355 days] vs. 194 days [95 % CI 45 days–not estimable]; P = 0.35). Conclusions The suggested upper threshold for the therapeutic window of everolimus Ctrough was 17.3 ng/mL. Pharmacokinetically guided dosing may improve the efficacy and safety of everolimus for mBC, warranting further investigation in a larger study.

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 Japan Research Foundation for Clinical Pharmacology.

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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. Breast Disease Center, Asahikawa Medical University Hospital, Asahikawa, Japan

    Kei Ishibashi & Masahiro Kitada

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  1. Masahide Fukudo
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  2. Kei Ishibashi
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  3. Masahiro Kitada
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Contributions

Study concept and design: M.F., M.K.; 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.I., M.K.; supervision: M.F.

Corresponding author

Correspondence to Masahide Fukudo.

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Ethics approval and consent to participate

The protocol of this study was approved by the institutional ethics committee of Asahikawa Medical University (#14085). The study was performed in accordance with the Declaration of Helsinki and its amendments. Written informed consent was obtained from each patient prior to participation in the study. 

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All authors approved the final version of the manuscript.

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All authors have no conflicts of interest to declare.

Research involving human participants

The protocol of this study was approved by the institutional ethics committee of Asahikawa Medical University (#14085). The study was performed in accordance with the Declaration of Helsinki and its amendments.

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

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Fukudo, M., Ishibashi, K. & Kitada, M. Real-world pharmacokinetics and pharmacodynamics of everolimus in metastatic breast cancer. Invest New Drugs 39, 1707–1715 (2021). https://doi.org/10.1007/s10637-021-01131-4

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