卡马西平在东北地区癫痫患者中的群体药代动力学模型建立与剂量选择
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摘要
目的根据癫痫患者卡马西平血药浓度,建立卡马西平群体药代动力学模型,为临床卡马西平个体化用药提供参考。方法收集2016年7月至2018年3月于我院进行常规监测卡马西平血药浓度的东北地区癫痫患者135例,共采集390个血药浓度作为建模依据。以年龄、性别、体重、服药日剂量、肝功能指标、合并用药等作为协变量,用一级吸收及消除的药代动力学模型,通过非线性混合效应模型(NONMEN)法建立癫痫患者卡马西平群体药代动力学模型并验证。用蒙特卡罗法根据群体药代动力学参数优化卡马西平给药剂量。结果剂量(TAMT)和合用丙戊酸钠(VPA)为卡马西平清除率(CL)的影响因素。最终模型为CL=0. 74×1. 50~(VPA)+(TAMT/473. 40)×1. 94 (合用丙戊酸VPA=1,否则VPA=0),合用丙戊酸的患者需要增加卡马西平给药剂量。结论卡马西平的清除率随剂量的增加以线性的方式增加,合并使用丙戊酸会增加卡马西平的清除率和剂量。所建模型稳定可靠,可用于临床卡马西平的个体化治疗。
Objective To establish the population pharmacokinetic model of carbamazepine in epileptic patients in northeast China according to its concentrations and provide references for individual medicine in clinical. Methods This study collected 135 epileptic patients of Northeast China treated with carbamazepine from Shengjing Hospital of China Medical University and 390 blood drug concentrations were used for a modeling basis. Covariates including age,sex,body weight,daily dose,liver function index,drug combination,etc,were investigated.The population pharmacokinetic model of carbamazepine was established using first-order absorption and elimination model by nonlinear mixed effect model( NONMEN) method. The final model was successfully verified. Monte Carlo simulations were performed to optimize dosage according population pharmacokinetic parameters of carbamazepine. Results Dosage( TAMT) and co-administration of valproate( VPA) were influencing factors of the clearance rate( CL) of carbamazepine. The final model formula was CL = 0. 74 × 1. 50 ~(VPA)+( TAMT/473. 40) × 1. 94,( concomitant with valproate,VPA = 1,otherwise VPA = 0). Dosage of carbamazepine should be increased when valproate was administrated.Conclusion There was a linear relationship between CL and dose ofcarbamazepine. The combined use of valproate could increase CL and dosage of carbamazepine. The established model was stable and reliable,which could be used for personalized therapy of carbamazepine.
Objective To establish the population pharmacokinetic model of carbamazepine in epileptic patients in northeast China according to its concentrations and provide references for individual medicine in clinical. Methods This study collected 135 epileptic patients of Northeast China treated with carbamazepine from Shengjing Hospital of China Medical University and 390 blood drug concentrations were used for a modeling basis. Covariates including age,sex,body weight,daily dose,liver function index,drug combination,etc,were investigated.The population pharmacokinetic model of carbamazepine was established using first-order absorption and elimination model by nonlinear mixed effect model( NONMEN) method. The final model was successfully verified. Monte Carlo simulations were performed to optimize dosage according population pharmacokinetic parameters of carbamazepine. Results Dosage( TAMT) and co-administration of valproate( VPA) were influencing factors of the clearance rate( CL) of carbamazepine. The final model formula was CL = 0. 74 × 1. 50 ~(VPA)+( TAMT/473. 40) × 1. 94,( concomitant with valproate,VPA = 1,otherwise VPA = 0). Dosage of carbamazepine should be increased when valproate was administrated.Conclusion There was a linear relationship between CL and dose ofcarbamazepine. The combined use of valproate could increase CL and dosage of carbamazepine. The established model was stable and reliable,which could be used for personalized therapy of carbamazepine.
引文
[1]郭志磊,于洋,宋红萍.高效液相色谱法同时测定人血浆中卡马西平、奥卡西平及其活性代谢产物的浓度和临床应用[J].中国医院药学杂志,2018,38(9):934-938.
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[3]焦正,钟明康,施孝金,等. NONMEM法估算中国癫痫患者卡马西平的清除率[J].中国药理学通报,2003,19(3):314-318.
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[8]宋艳,芮建中,陈文瑛,等.非线性混合效应模型法估算癫痫患者卡马西平的群体药代动力学参数[J].中国药房,2010,21(32):3024-3027.
[9] REITH D M,HOOPER W D,PARKE J,et al. Population pharmacokinetic modeling of steady state carbamazepine clearance in children,adolescents,and adults[J]. J Pharmacokinet Pharmacodyn,2001,28(1):79-92.
[2]朱旭,张媞,田敏,等.高效液相色谱法和荧光偏振免疫法测定卡马西平血药浓度的比较分析[J].中国临床药理学杂志,2016,32(1):68-71.
[3]焦正,钟明康,施孝金,等. NONMEM法估算中国癫痫患者卡马西平的清除率[J].中国药理学通报,2003,19(3):314-318.
[4]朱旭,刘美,刘立民,等. HPLC-UV法同时测定卡马西平及其主要代谢物的血药浓度[J].中国临床药理学杂志,2013,29(11):853-885.
[5] CHAN E,LEE H S,HUE S S. Population pharmacokinetics of carbamazepine in Singapore epileptic patients[J]. Br J Clin Pharmacol,2001,51(6):567-576.
[6]杨爱芳.卡马西平PPK模型预测能力的评价与临床应用研究[D].上海:复旦大学,2014.
[7] YUKAWA E,AOYAMA T. Detection of carbamazepine drug interaction by multiple peak approach screening using routine clinical pharmacokinetic data[J]. J Clin Pharmacol,1996,36(8):752-759.
[8]宋艳,芮建中,陈文瑛,等.非线性混合效应模型法估算癫痫患者卡马西平的群体药代动力学参数[J].中国药房,2010,21(32):3024-3027.
[9] REITH D M,HOOPER W D,PARKE J,et al. Population pharmacokinetic modeling of steady state carbamazepine clearance in children,adolescents,and adults[J]. J Pharmacokinet Pharmacodyn,2001,28(1):79-92.