卡培他滨在结直肠癌患者中的群体药动学研究

Population pharmacokinetics of capecitabine in colorectal cancer patients

目的评价卡培他滨在肠癌患者的群体药动学特征及可能的影响因素。方法选取56例肠癌(包括结肠癌及直肠癌)患者为研究对象,餐后单次口服卡培他滨0.6g(0.15g×4片)后进行多点采集血样,以高效液相色谱-质谱联用法(HPLC-MS/MS)检测受试者给药后血浆中的卡培他滨的血药浓度,以非线性混合效应模型及程序(NONMEM)对检测数据进行分析,建立卡培他滨群体药动学模型并获得其群体药动学参数。结果最终模型为一级吸收和消除的一室模型,模型的药动学参数群体典型值为:清除率(CL)为265 L/h,表观分布容积(V)为329 L,吸收速率常数(Ka)为2.15 h^(-1)。人口统计学因素(年龄、性别、体质量等)及肝肾清除相关因素(肌酐清除率、胆红素及白蛋白等)对卡培他滨的清除均无显著性影响。结论所得模型稳定,能较好地拟合卡培他滨在肠癌患者的的群体药动学特征,可用于临床个体化给药方案的制订。

Objective To investigate the population pharmacokinetic characteristics of capecitabine and its possible influencing factors in colorectal cancer patients.Methods 56 colorectal cancer patients were chosen as the research objects.After a single dose of 0.6 g(0.15 g,4 tablets,orally)of capecitabine tablets,blood samples were collected from multiple sites,the plasma concentration of capecitabine was determined by HPLC-MS/MS.The nonlinear mixed effect model and program(NONMEM)were used to analyze the data,the population pharmacokinetic model of capecitabine was established and its population pharmacokinetic parameters were obtained.Results The final model is one-compartment model with first order absorption and elimination.Population typical pharmacokinetic parameters of the model:clearance(CL)is 265 L/h,apparent volume of distribution(V)is 329 L,and the absorption rate constant(Ka)is 2.15 h^(-1).Demographic factors(age,gender,body weight,etc.)and liver kidney clearance related factors(creatinine clearance rate,bilirubin and albumin,etc.)have no significant effect on the clearance of capecitabine.Conclusion The model is stable and can well fit the population pharmacokinetic characteristics of capecitabine in Chinese patients with colorectal cancer,which can be used for developing a individualized administration scheme in clinical.