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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 10/2016

01-10-2016 | Original Research Article

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

Authors: Yuxiang Ma, Yuehao Lin, Benyan Zou, Wanli Liu, Yang Zhang, Liping Zhao, Yan Huang, Yunpeng Yang, Wenfeng Fang, Yuanyuan Zhao, Jin Sheng, Tao Qin, Zhihuang Hu, Li Zhang, Hongyun Zhao

Published in: Clinical Pharmacokinetics | Issue 10/2016

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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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Metadata
Title
Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma
Authors
Yuxiang Ma
Yuehao Lin
Benyan Zou
Wanli Liu
Yang Zhang
Liping Zhao
Yan Huang
Yunpeng Yang
Wenfeng Fang
Yuanyuan Zhao
Jin Sheng
Tao Qin
Zhihuang Hu
Li Zhang
Hongyun Zhao
Publication date
01-10-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 10/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0395-2

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