title: Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Yuehao
authors.initials: Y
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Benyan
authors.initials: B
authors.lastname: Zou
authors.affiliation: 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.
authors.forename: Wanli
authors.initials: W
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Yue Bei People's Hospital, Shaoguan, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Fang
authors.affiliation: 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.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Sheng
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Zhihuang
authors.initials: Z
authors.lastname: Hu
authors.forename: Salavatore J
authors.initials: SJ
authors.lastname: Salamone
authors.forename: Yunying
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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. zhangli63@hotmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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. zhaohy@sysucc.org.cn.
authors.forename: Hongyun
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D044466:Asian People; D002277:Carcinoma / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005202:Asia, Eastern; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D012333:RNA, Messenger / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000096:biosynthesis
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D002945:Cisplatin; D005472:Fluorouracil