成人肝移植术后他克莫司群体药动学研究
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摘要
目的:应用非线性混和效应模型考察中国肝移植患者他克莫司群体药动学特征。方法:回顾收集天津市第一中心医院成人肝移患者57例,1 094个他克莫司谷浓度点,验证组患者10例,183个谷浓度点。采用一房室模型,分析处理数据,采用NPDE、Bootstrap和外部验证的方法对模型进行评估。结果:最终模型显示血红蛋白(HGB)和术后时间(POD)为影响清除率的主要因素。药动学参数的群体典型值:清除率(CL/F)估算值为19.8 L·h~(-1),表观分布容积估算值为597 L。模型评价显示该模型及所估算参数稳定。结论:本研究所建立的成人肝移植受者口服他克莫司的群体药动学模型能较好地估算患者的个体及群体药动学参数,为今后肝移植患者个体化给药方案的制订提供相关参考。
OBJECTIVE To investigate the population pharmacokinetics of tacrolimus in Chinese liver transplant patients by using a nonlinear mixed effect model. METHODS A retrospective study was conducted on 57 adult patients with liver metastases in Tianjin First Center Hospital with 1094 tacrolimus trough concentration points and 10 patients in validation group with 183 trough concentration points. A one-compartment model with first order elimination was used to analyze the processed data, and the model was assessed using NPDE, bootstrap, and external validation methods. RESULTS The final model showed that the hemoglobin(HGB) and postoperative time(POD) were identified as the main factors affecting clearance. Population typical values for pharmacokinetic parameters: estimated clearance(CL/F) of 19.8 L·h~(-1) and estimated apparent volume of distribution of 597 L.Model evaluation showed that the model and the estimated parameters were stable. CONCLUSION The population pharmacokinetic model of oral tacrolimus in adult liver transplant recipients could better estimate individual and population pharmacokinetic parameters,and provide relevant reference for the development of individualized dosing regimen for liver transplant patients in the future.
OBJECTIVE To investigate the population pharmacokinetics of tacrolimus in Chinese liver transplant patients by using a nonlinear mixed effect model. METHODS A retrospective study was conducted on 57 adult patients with liver metastases in Tianjin First Center Hospital with 1094 tacrolimus trough concentration points and 10 patients in validation group with 183 trough concentration points. A one-compartment model with first order elimination was used to analyze the processed data, and the model was assessed using NPDE, bootstrap, and external validation methods. RESULTS The final model showed that the hemoglobin(HGB) and postoperative time(POD) were identified as the main factors affecting clearance. Population typical values for pharmacokinetic parameters: estimated clearance(CL/F) of 19.8 L·h~(-1) and estimated apparent volume of distribution of 597 L.Model evaluation showed that the model and the estimated parameters were stable. CONCLUSION The population pharmacokinetic model of oral tacrolimus in adult liver transplant recipients could better estimate individual and population pharmacokinetic parameters,and provide relevant reference for the development of individualized dosing regimen for liver transplant patients in the future.
引文
[1] Mould DR,D’Haens G,Upton RN.Clinical Decision Support Tools:The Evolution of a Revolution[J].Clin Pharmacol Ther,2016,99(4):405-418.
[2] Venkataramanan R,Swaminathan A,Prasad T,et al.Clinical pharmacokinetics of tacrolimus[J].Clin Pharmacokinet,1995,29(6):404-430.
[3] Shao J,Jiao Z,Ding J,et al.Bibliometric analysis and research status summary for pharmacometrics in China[J].Chin Hosp Pharm J(中国医院药学杂志),2018,38 (7):687-692.
[4] Shao J,Jiao Z,Wei JX,et al.The progress of population pharmacokinetics in adult liver transplantation oral tacrolimus recipients[J].Chin Pharmacol J (中国药学杂志),2018,53(17):1433-1437.
[5] Zhang XQ,Wang ZW,Fan JW,et al.The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in Chinese adult liver-transplant patients[J].Ther Drug Monit,2012,34 (2):126-133.
[6] Staatz CE,Willis C,Taylor PJ,et al.Population pharmacokinetics of tacrolimus in adult kidney transplant recipients[J].Clin Pharmacol Ther,2002,72 (6):660-669.
[7] Circular of General Administration on guiding principles for general consideration of drug clinical trials (总局关于发布药物临床试验的一般考虑指导原则的通告)[EB/OL].[2017-1-18].http://www.sda.gov.cn/WS01/CL0087/168752.html.
[8] Lee JY,Hahn HJ,Son IJ,et al.Factors Affecting the Apparent Clearance of Tacrolimus in Korean Adult Liver Transplant Recipients[J].Pharmacotherapy,2006,26(8):1069-1077.
[9] Antignac M,Hulot JS,Boleslawski E,et al.Population pharmacokinetics of tacrolimus in full liver transplant patients:modelling of the post-operative clearance[J].Eur J Clin Pharmacol,2005,61(5-6):409-416.
[10] Zhang LH,Song HY,Qin Y.Correlation analysis between relative clearance rate of tacrolimus and clinical factors[J].Chin Med J Metall Indus(中国冶金工业医学杂志),2013,30(1):32-33.
[11] Chen YH,Zheng KL,Chen LZ,et al.Correlation between relative clearance rate of tacrolimus and clinical factors[J].Guangdong Med J (广东医学),2005,26 (2):188-190.
[12] Zahir H,McLachlan A J,Nelson A,et al.Population pharmacokinetic estimation of tacrolimus apparent clearance in adult liver transplant recipients[J].Ther Drug Monit,2005,27 (4):422-430.
[13] Zhang XQ,Wang ZW,Fan JW,et al.The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in Chinese adult liver-transplant patients[J].Ther Drug Monit,2012,34 (2):126-133.
[14] Zhang Y,Peng F,Zheng H,et al.Population Pharmacokinetics of Tacrolimus in Chinese Recipients with Liver Transplantation[J].Chin Pharmacol J (中国药学杂志),2008,43 (24):1897-1902.
[2] Venkataramanan R,Swaminathan A,Prasad T,et al.Clinical pharmacokinetics of tacrolimus[J].Clin Pharmacokinet,1995,29(6):404-430.
[3] Shao J,Jiao Z,Ding J,et al.Bibliometric analysis and research status summary for pharmacometrics in China[J].Chin Hosp Pharm J(中国医院药学杂志),2018,38 (7):687-692.
[4] Shao J,Jiao Z,Wei JX,et al.The progress of population pharmacokinetics in adult liver transplantation oral tacrolimus recipients[J].Chin Pharmacol J (中国药学杂志),2018,53(17):1433-1437.
[5] Zhang XQ,Wang ZW,Fan JW,et al.The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in Chinese adult liver-transplant patients[J].Ther Drug Monit,2012,34 (2):126-133.
[6] Staatz CE,Willis C,Taylor PJ,et al.Population pharmacokinetics of tacrolimus in adult kidney transplant recipients[J].Clin Pharmacol Ther,2002,72 (6):660-669.
[7] Circular of General Administration on guiding principles for general consideration of drug clinical trials (总局关于发布药物临床试验的一般考虑指导原则的通告)[EB/OL].[2017-1-18].http://www.sda.gov.cn/WS01/CL0087/168752.html.
[8] Lee JY,Hahn HJ,Son IJ,et al.Factors Affecting the Apparent Clearance of Tacrolimus in Korean Adult Liver Transplant Recipients[J].Pharmacotherapy,2006,26(8):1069-1077.
[9] Antignac M,Hulot JS,Boleslawski E,et al.Population pharmacokinetics of tacrolimus in full liver transplant patients:modelling of the post-operative clearance[J].Eur J Clin Pharmacol,2005,61(5-6):409-416.
[10] Zhang LH,Song HY,Qin Y.Correlation analysis between relative clearance rate of tacrolimus and clinical factors[J].Chin Med J Metall Indus(中国冶金工业医学杂志),2013,30(1):32-33.
[11] Chen YH,Zheng KL,Chen LZ,et al.Correlation between relative clearance rate of tacrolimus and clinical factors[J].Guangdong Med J (广东医学),2005,26 (2):188-190.
[12] Zahir H,McLachlan A J,Nelson A,et al.Population pharmacokinetic estimation of tacrolimus apparent clearance in adult liver transplant recipients[J].Ther Drug Monit,2005,27 (4):422-430.
[13] Zhang XQ,Wang ZW,Fan JW,et al.The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in Chinese adult liver-transplant patients[J].Ther Drug Monit,2012,34 (2):126-133.
[14] Zhang Y,Peng F,Zheng H,et al.Population Pharmacokinetics of Tacrolimus in Chinese Recipients with Liver Transplantation[J].Chin Pharmacol J (中国药学杂志),2008,43 (24):1897-1902.