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Paclitaxel exposure-toxicity analysis reveals a pharmacokinetic determinant for dose-limiting neutropenia in East-Asian solid tumor patients: results from two prospective, phase II studies

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Abstract

Purpose

The time of a paclitaxel (PTX) concentration remains above 0.05 μM (Tc > 0.05) has been associated with PTX-induced adverse effects in Caucasians, while limited studies were reported in Asians. This study was aimed to explore the characteristics of Tc > 0.05 and the relationship between PTX exposure and toxicity in East-Asian patients.

Methods

This study was based on two prospective phase II clinical trials and patients with advanced nasopharyngeal cancer (NPC) and non-small cell lung cancer (NSCLC) who were naïve to PTX were included independently. Eligible patients receive PTX (175 mg/m2) and carboplatin (AUC = 5) treatment every 3 weeks. PTX pharmacokinetic analysis was accessed. The relationship between PTX exposure and toxicities after first cycle as well as clinical efficacy was evaluated.

Results

A total of 93 NPC and 40 NSCLC patients were enrolled. PTX exposure was consistent in two trials with average Tc > 0.05 duration of 38.8 h and 38.4 h, respectively. Average Tc > 0.05 in patients with grade 3/4 neutropenia was significantly higher than those without severe neutropenia in NPC patients (P = 0.003) and NSCLC patients (P = 0.007). Cut-off value of Tc > 0.05 were identified from the NPC cohort and then verified in the NSCLC cohort, dividing patients into high exposure Tc > 0.05 group (> 39 h) and low exposure group (≤ 39 h). Incidence of grade 3/4 neutropenia were significantly higher in the high exposure group in NPC cohort (43.3% vs 10.0%, P < 0.001) and NSCLC cohort (42.1% vs 9.5%, P = 0.028). No significant relationship between Tc > 0.05 and efficacy were observed.

Conclusion

Patients with PTX Tc > 0.05 duration above 39 h experience more severe neutropenia than those under 39 h. Prospective studies are needed to verify this threshold.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

The authors gratefully thank the patients and their families, study investigators, and personnel who participated in this trial.

Funding

This work was supported by National Nature Science Foundation of China (Grant Number: 81872499 for L Zhang, Grant Number: 82002409 for Y Ma, Grant Number: 82073396 for H Zhao), Guangdong Basic and Applied Basic Research Foundation (2020A1515010020 for Y Ma), and Bristol-Myers Squibb.

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Author notes

  1. Jinhui Xue, Haipeng He, Zuan Lin and Yuehan Wu have contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651 East Dongfeng Road, Guangzhou, 510060, China

    Jinhui Xue, Zuan Lin, Yuehan Wu, Hongyun Zhao, Yang Zhang & Yuxiang Ma

  2. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651 East Dongfeng Road, Guangzhou, 510060, China

    Yan Huang, Yunpeng Yang, Wenfeng Fang, Shaodong Hong & Li Zhang

  3. The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Haipeng He

  4. Department of Laboratory, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    Yuehao Lin

  5. Saladax Biomedical Inc., Bethlehem, USA

    Salvatore J. Salamone

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  1. Jinhui Xue
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Xue, J., He, H., Lin, Z. et al. Paclitaxel exposure-toxicity analysis reveals a pharmacokinetic determinant for dose-limiting neutropenia in East-Asian solid tumor patients: results from two prospective, phase II studies. Cancer Chemother Pharmacol 90, 229–237 (2022). https://doi.org/10.1007/s00280-022-04456-w

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