卡培他滨在中国乳腺癌患者中的群体药代动力学研究

Population pharmacokinetics of capecitabine in Chinese breast cancer patients

目的:评价卡培他滨在中国乳腺癌患者的群体药代动力学特征及可能的影响因素。方法:选取78例中国乳腺癌患者为研究对象,餐后单次口服卡培他滨片0.6 g(0.15 g/片,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)检测血浆中卡培他滨的血药浓度,以非线性混合效应软件及模型(NONMEM)对检测数据进行分析,建立卡培他滨群体药代动力学模型并获得其群体药代动力学参数。结果:最终建立的吸收及消除模型为一室模型,模型的清除率(CL/F)药代动力学公式为:CL/F=291×e^(ηCL)×(CCR÷93.1)^(0.47)。群体药代动力学参数如下:CL/F为291 L/h,表观分布容积(V/F)为556 L,吸收速率常数(K_(a))为1.05 h^(-1)。同时发现,肌酐清除率(CCR)对卡培他滨的清除有显著影响。结论:所得模型稳定,能较好地拟合卡培他滨在中国乳腺癌患者的群体药代动力学特征,可用于临床个体化给药方案的制订。

AIM:To investigate the population pharmacokinetic characteristics of capecitabine and its possible influencing factors in Chinese patients of breast cancer.METHODS:78 cases of Chinese patients with breast cancer were chosen as the objects in this study.Following treatment with capecitabine(0.6 g,0.15 g/piece,4 pieces,orally),blood samples were collected and concentrations of capecitabine in plasma were analyzed by high performance liquid chromatography-mass spectrometry(HPLC-MS/MS)method.The nonlinear mixed-effects software(NONMEM)was used to analyze the data and the population pharmacokinetic model was constructed accordingly.RESULTS:The final established model of absorption and elimination is one-compartment model.The clearance(CL/F)in pharmacokinetic formula of the model is as follows:CL/F=291×e^(ηCL,i)×(CCR÷93.1)^(0.47).The typical pharmacokinetic parameters of the model are as follows:the clearance(CL/F)is 291 L/h;the apparent volume of distribution(V/F)is 556 L;the absorption rate constant(K_(a))is 1.05 h^(-1).In addition,the elimination of capecitabine can be notably influenced by creatinine clearance rate(CCR).CONCLUSION:The constructed model is stable,which fits features well of the population pharmacokinetics of capecitabine in Chinese patients with breast cancer.The modle can be utilized for the individualized administration plan in clinic.