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Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer

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Abstract

Purpose

The objective of this study was to investigate the pharmacokinetic characteristics of pegylated liposomal doxorubicin (PLD) in Chinese female patients with advanced breast cancer by constructing population pharmacokinetic (popPK) models of liposome-encapsulated and free doxorubicin. Additionally, the relationship between pharmacokinetic parameters and drug-related adverse events (AEs) was explored through toxicity correlation analysis.

Methods

A total of 20 patients with advanced breast cancer were selected from a PLD bioequivalence study. All patients received a single intravenous dose of 50 mg/m2 PLD. Plasma concentrations were measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS). A popPK model was simultaneously built to characterize the pharmacokinetic profiles of liposome-encapsulated and free doxorubicin by non-linear mixed effects model (NONMEM). PLD-related toxicities were graded according to the common terminology criteria for adverse events (CTCAE) v5.0. The Spearman correlation analysis was conducted to explore the relationship between pharmacokinetic parameters and drug-related AEs of both liposome-encapsulated doxorubicin and free doxorubicin.

Results

The concentration–time profiles of both liposome-encapsulated doxorubicin and free doxorubicin were well described by a one-compartment model. The most common AEs to PLD were nausea, vomiting, neutropenia, leukopenia, and stomatitis, most of which were grade I–II. The toxicity correlation analysis results indicated that stomatitis was related to the Cmax of liposome-encapsulated doxorubicin (P < 0.05). No other AEs were found to be correlated with the pharmacokinetic parameters of either free or liposome-encapsulated doxorubicin.

Conclusion

A one-compartment model adequately described the popPK characteristics of both liposome-encapsulated and free doxorubicin in Chinese female patients with advanced breast cancer. Most AEs to PLD were mild. Additionally, the occurrence of mucositis may be positively correlated with the Cmax of liposome-encapsulated doxorubicin.

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Data availability statement

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank all the patients and their families for participating in the studies. The authors also thank Professor Tianyan Zhou for her assistance in modeling and simulating in this popPK analysis.

Funding

This study was supported by the National Natural Science Foundation of China under grant Nos. 81973396, 82003851, and 82274020, the Zhejiang Provincial Medical Health Science and Technology Project under Grant No. 2022KY107, and the Hospital Pharmacy Special Project of Zhejiang Pharmaceutical Association under Grant No. 2021ZYY19.

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Author notes

  1. Gaoqi Xu and Dihong Yang have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China

    Gaoqi Xu, Dihong Yang, Chaoneng He, Like Zhong, Junfeng Zhu, Qi Shu, Haiying Ding, Wenxiu **n, Yinghui Tong & Luo Fang

  2. Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China

    **ao Zhu

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  1. Gaoqi Xu
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Correspondence to **ao Zhu or Luo Fang.

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The studies involving human participants were reviewed and approved by the Ethics Committee of the Fourth Hospital of Hebei Medical University, Affiliated Hospital of Hebei University and Henan Cancer Hospital. The patients provided their written informed consent to participate in this study.

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Xu, G., Yang, D., He, C. et al. Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer. Cancer Chemother Pharmacol 92, 181–192 (2023). https://doi.org/10.1007/s00280-023-04559-y

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