【摘要】 目的观察辛伐他汀在稳定血液透析患者的药物代谢动力学特征,以及可能的影响因素。方法稳定血液透析患者一次性服用辛伐他汀20 mg,用药后不同时间采血,用HPLC-MS/MS测定辛伐他汀血药浓度,以非线性混合效应模型法(NONMEM)进行分析,得到群体药代动力学参数,并与文献中正常人辛伐他汀药代动力学参数进行比较。结果共23例患者参加该研究,获得95份血样,平均年龄60.48岁。最终模型的药代动力学参数估计值(95%可信区间)分别为,CL1为663(375～951)L.h-1;CL2为197(42.7～351)L.h-1,V1为119(32.2～206)L;V2为1830(905～2760)L;Ka为0.59(0.37～0.82)h-1;Tlag为0.49(0.48～0.50)h。血液透析器(滤器)、吸烟、体重指数可能影响药物的清除率。推算患者的药代动力学参数,t1/2为(6.83±10.79)h;Cmax为(12.25±8.35)μg·L-1;tmax为(0.90±0.27)h;AUC0→t为(30.80±25.00)μg·h.L-1。结论本研究所得群体药代动力学模型可能实现血透患者辛伐他汀个体化药物调整。更多还原

【Abstract】 Objective To investigate the population pharmacokinetic characteristics of simvastatin in hemodialysis patients and factors covariables that might impact its clearance.Methods The qualified maintenance hemodialysis patients took simvastatin 20 mg orally once and then 2-4 serum samples were collected at different time.The serum simvastatin concentration was measured with the method of HPLC-MS/MS and analysed with nonlinear mixed-effect model(NONMEM).The population pharmacokinetics parameters were compared with those of healthy volunteers in literatures.Results A total of 23 patients took simvastatin and contributed 95 serum samples.There were eleven male cases.The mean age was 60.48 years.NONMEM demonstrated that the data were fit for two-compartment model.Typical population estimates(95% confidence intervals) of CL1,CL2,V1,V2,Ka and Tlag were 663(375-951)L.h-1,197(42.7-351) L.h-1,119(32.2-206) L,1830(905 2760) L,0.59(0.37-0.82) h-1,0.49(0.48-0.50) h,respectively.Dialyzer,smoking,body mass index might impact the simvastatin clearance rate.The extrapolated pharmacokinetics parameters t 1 /2,C max,t max,AUC 0→t were(6.83 ± 10.79) h,(12.25 ± 8.35) μg.L-1,(0.90 ± 0.27) h,(30.80 ± 25.00) μg.h.L-1,respectively.Conclusion The population pharmacokinetic model of simvastatin by NONMEM was proved to be reliable.It might realize the simvastatin dosage individualation in hemodialysis patients.This study demonstrated that the AUC with simvastatin(20 mg) was similar to that of healthy volunteers with simvastatin 40 mg orally in literatures.It recommends that simvastatin should be administered individully and less legular initial dose might be used in hemodialysis patients.更多还原