5-氟尿嘧啶在头颈部肿瘤病人体内的群体药动学研究(英文)  

5- Fluorourouracil in head and neck cancer: a popupation pharmacokinetics study

作　　者：杨晨光 Ciccolini Josephe 许鹏 鱼麦侠 谢燕华 孙婧 Mercier Cedric 陈捷 

机构地区：[1]陕西省中医医院肿瘤科,陕西西安710002 [2]La Timone大学医院临床和药理学联盟,法国marseille13385 [3]La Timone大学医院肿瘤内科,法国marseille13385

出　　处：《现代肿瘤医学》2013年第12期2661-2666,共6页Journal of Modern Oncology

基　　金：陕西省科学研究发展计划支持项目(编号:2011k13-01-06)

摘　　要：目的:二氢嘧啶脱氢酶(DPD)缺乏是导致5-FU毒性的主要原因。我们根据病人DPD状态调节5-FU的使用剂量,减少了毒副作用而没有影响疗效。当前的工作目标是确定5-FU药动学的合变量并为它建立一个新的模型。方法:本研究纳入22个头颈部肿瘤患者,根据DPD状态调节5-FU的剂量,利用NONMEM V5计算群体和个体的药动学参数。结果:在本组病人中,5-FU的药动学被描述为线性的、利用一级条件评估法和混合误差模型构成的一室模型。影响5-FU清除的主要合变量首先是体表面积。DPD状态对5-FU清除的影响出现在64%的病人中。DPD状态比年龄、性别等经常与5-FU毒性相关的合变量更能影响5-FU的清除。结论:在基于DPD的5-FU剂量调整战略的病人中,预先确定DPD不足的病人已被初筛并调整剂量,从而影响了5-FU的药动学。当DPD的问题被预先处理后,体表面积成为调节5-FU剂量的相关合变量。Objective：A major cause for 5 - FU severe toxicities is a pharmacogenetic syndrome known as dihy- dropyrimidine dehydrogenase （ DPD ） deficiency, affecting the ability of patients to detoxify standard dosages. 5 - FU dosage was adjusted in patients in accordance with their DPD status, thus reducing toxicity witilout affecting treatment efficacy. The present work aims at identifying the effect of covariates on 5 - FU pharmacokinetics（PK） and developing a new model for it. Methods：This retrospective study was carried out on 22 patients treated for head and neck cancer with adjusting dosage of 5 - FU. Population and individual pharmacokinetics parameters were computed using a NON- MEM V5 program. Result：In all patients, pharmacokinetics of 5 -FU was best described by a linear, one compartment model using first order conditional estimation（FOCE） interaction method and a mixed error model. The main covariate of 5 - FU clearance was body surface area（BSA）. Conversely ,impact of DPD status on 5 - FU elimination was found in a subset of 64% patients. Impact of DPD status was found to be greater than age or sex,which are demographic co- variates usually associated with risk of developing toxicities upon 5 - FU intake. Conclusion ： In patients with DPD - based 5 - FU dosing strategy, drug pharmacokinetics becomes linear as saturation of DPD - mediated catabolic path- way is prevented by the preliminary identification of deficient patients. When the DPD issue is addressed preliminary, BSA is a relevant covariate to adjust 5 - FU dosage.

关 键 词：群体药物动力学 二氢嘧啶脱氢酶(DPD) 头颈部肿瘤 NONMEM分析 

分 类 号：R73-361[医药卫生—肿瘤] R739.6[医药卫生—临床医学]