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Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma

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An Author Correction to this article was published on 26 December 2017

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Abstract

Background and Objective

5-Fluorouracil plus cisplatin is the most commonly used chemotherapy regimen for nasopharyngeal carcinoma (NPC). The objective of this study was to establish an individualized 5-fluorouracil treatment model based on pharmacokinetic and pharmacodynamic analyses of 5-fluorouracil in East-Asian NPC patients.

Methods

A total of 122 NPC patients were administered 5-fluorouracil plus cisplatin treatment. Blood samples were collected to calculate the area under the concentration–time curve (AUC) for 5-fluorouracil, and expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) at both protein and messenger RNA (mRNA) levels were analyzed in the tumor tissues from 73 patients in the same cohort.

Results

The results showed a wide (sevenfold) pharmacokinetic variability of 5-fluorouracil exposure (measured as AUC) based on body surface area (BSA) dosing. Pharmacokinetic analyses revealed that the 5-fluorouracil AUC range had a significant impact on the response of patients to 5-fluorouracil and related toxicities. Patients with 5-fluorouracil AUC <25 mg·h/L responded unsatisfactorily to 5-fluorouracil (overall response rate [ORR] 17.5 % lower than patients with AUC 25–35, p = 0.176; and 26.1 % lower than patients with AUC >35, p = 0.031). On the other hand, patients with 5-fluorouracil AUC >35 mg·h/L experienced more 5-fluorouracil-related toxicities (a grade 3 or higher toxicity rate 57.1 % higher than patients with AUC 25–35, p < 0.001; and 60.0 % higher than AUC >35, p < 0.001). The established 5-fluorouracil therapeutic window in head and neck cancer (HNC) [AUC 25–35 mg·h/L) was verified in our study. Pharmacodynamic analyses indicated a positive correlation between TS and DPD expression (p < 0.001) and, despite the pharmacokinetic influences, low expression of TS mRNA in tumor tended to have a better ORR (81.0 vs. 54.3 %, p = 0.051). No significant association was found between DPD expression and ORR.

Conclusions

The therapeutic window of 5-fluorouracil for East–Asian NPC patients was verified as 25–35 mg·h/L based on lower toxicity and higher efficacy. TS mRNA expression showed potentially predictive value in 5-fluorouracil treatment, and personalized treatment based on pharmacokinetics and pharmacodynamics proved to be clinically beneficial and is worthy of further clinical studies.

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  • 26 December 2017

    Page 1205, the author names and affiliations which previously read

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Author notes

    Authors and Affiliations

    1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Clinical Trial Center, Sun Yat-Sen University Cancer Center, 651# Dongfeng Road East, Guangzhou, 510060, China

      Yuxiang Ma, Yang Zhang & Hongyun Zhao

    2. Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651# Dongfeng Road East, Guangzhou, 510060, China

      Benyan Zou, Yan Huang, Yunpeng Yang, Wenfeng Fang, Yuanyuan Zhao, Jin Sheng, Tao Qin, Zhihuang Hu & Li Zhang

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

      Yuehao Lin & Wanli Liu

    4. Department of Medical Oncology, Yue Bei People’s Hospital, Shaoguan, China

      Liping Zhao

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    1. Yuxiang Ma
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    3. Benyan Zou
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    Corresponding authors

    Correspondence to Li Zhang or Hongyun Zhao.

    Ethics declarations

    This study was supported by the National Natural Science Foundation of China (Grant No. 81201718), Molecular Classification, Personalized Diagnosis and Therapy of Nasopharyngeal Carcinoma (Grant No: 2006AA02A404), and the National High Technology Research and Development Program of China (Grant No: 2012AA02A501). We are grateful to the patients and their families for their participation in this study.

    Conflict of interest

    Yuxiang Ma, Yuehao Lin, Benyan Zoub, Wanli Liu, Yang Zhang, Liping Zhao, Yan Huang, Yunpeng Yang, Wenfeng Fang, Yuanyuan Zhao, Jin Sheng, Tao Qin, Zhihuang Hu, Li Zhang, and Hongyun Zhao declare that they have no commercial or associative interests that represent a conflict of interest in connection with the work submitted.

    Additional information

    Y. Ma, Y. Lin, and B. Zou contributed equally to this work, and all three are considered to be first authors.

    A correction to this article is available online at https://doi.org/10.1007/s40262-017-0615-4.

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    Ma, Y., Lin, Y., Zou, B. et al. Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma. Clin Pharmacokinet 55, 1205–1216 (2016). https://doi.org/10.1007/s40262-016-0395-2

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