氯沙坦及其活性代谢物E-3174在中国不同民族健康人群中的群体药代动力学研究

doi:10.5246/jcps.2014.08.071

中国药学(英文版) ›› 2014, Vol. 23 ›› Issue (8): 548-557.DOI: 10.5246/jcps.2014.08.071

氯沙坦及其活性代谢物E-3174在中国不同民族健康人群中的群体药代动力学研究

杨璐¹, 孙路路¹, 郭涛^2*, 夏东亚², 王曦培³, 李新刚⁴, 卢炜⁵

1. 首都医科大学附属北京世纪坛医院药剂科, 北京 100038
2. 沈阳军区总医院药剂科, 辽宁沈阳 110016
3. 广东省人民医院 (广东省医学科学院), 广东广州 510080
4. 首都医科大学附属北京天坛医院药剂科, 北京 100050
5. 北京大学医学部药学院, 北京 100191

收稿日期:2014-03-03 修回日期:2014-04-01 出版日期:2014-08-31 发布日期:2014-04-21
通讯作者: Tel.: 86-24-28856331
基金资助:
The 115^th Project of Legionary Medical Treatment and Public Health (Grant No. 06G023).

Population pharmacokinetic of losartan and its active metabolite E-3174 in five different ethnic populations of China

Lu Yang¹, Lulu Sun¹, Tao Guo^2*, Dongya Xia², Xipei Wang³, Xingang Li⁴, Wei Lu⁵

1. Department of Pharmacy, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China
2. Department of Pharmacy, Shenyang Northern Hospital, Shenyang 110016, China
3. Guangdong general hospital (Guangdong academy of medical sciences), Guangzhou 510080, China
4. Department of Pharmacy, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing 100050, China
5. School of Pharmaceutical Science, Peking University Health Sciences Center, Beijing 100191, China

Received:2014-03-03 Revised:2014-04-01 Online:2014-08-31 Published:2014-04-21
Contact: Tel.: 86-24-28856331
Supported by:
The 115^th Project of Legionary Medical Treatment and Public Health (Grant No. 06G023).

摘要/Abstract

摘要：

建立氯沙坦及其活性代谢物E-3174在中国不同民族中的群体药代动力学模型, 为临床个体化用药提供参考。采用HPLC荧光法同时测定氯沙坦及E-3174的血药浓度。应用非线性混合效应模型法 (nonlinear mixed-effect modeling, NONMEM), 分别尝试单室、二室和三室模型拟合来自50个中国健康受试者 (包括汉族、蒙古族、朝鲜族、回族和维吾尔族)的血浆药物浓度-时间数据。采用正向模型化和逆向剔除的方法逐一考查了人口统计学和生化指标对氯沙坦基础模型的影响。氯沙坦的最终模型和E-3174间采用一级动力学或转运隔室模型进行连接。在组合模型中对氯沙坦及其活性代谢物E-3174的药物动力学参数进行拟合, 考察协变量对E-3174关键药代动力学参数的影响。非参数bootstrap法对模型的稳定性进行验证。线性消除的二室模型可较好拟合氯沙坦的数据。氯沙坦及其代谢物E-3174达峰时间分别为0.9和3.8小时。两个转运隔室可准确拟合E-3174滞后的达峰时间。群体拟合结果显示约有73.9%的氯沙坦转化为E-3174。民族因素能显著影响氯沙坦的清除率CL₁₀、隔室间清除率CL₂和中心室的表观分布容积V₁以及氯沙坦向E-3174的转运速率常数(Kt)。1000次的bootstrap中有925次收敛成功。群体药代动力学模型经过验证稳定可靠。民族因素显著影响氯沙坦的清除率和氯沙坦向E-3174的转化, E-3174的药代动力学参数不受任何因素的影响。

关键词: 氯沙坦, E-3174, 群体药代动力学, 非线性混合效应模型, 民族

Abstract:

The aim of this study was to develop a combined population pharmacokinetic (PPK) model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects (including Han, Mongolian, Korean, Hui and Uigur) using nonlinear mixed-effect modeling (NONMEM). From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokineticparameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach C_maxof losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed T_maxof E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL₁₀, the peripheral compartment clearance CL₂ and the central compartment volume V₁of losartan and also has a significant effect on the transit rate (Kt). A total of 925 out of 1000 iterations succeeded in minimization.The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.

Key words: Losartan, E-3174, Population pharmacokinetics, NONMEM, Ethnicity

中图分类号:

R969

Supporting:

杨璐, 孙路路, 郭涛, 夏东亚, 王曦培, 李新刚, 卢炜. 氯沙坦及其活性代谢物E-3174在中国不同民族健康人群中的群体药代动力学研究[J]. 中国药学(英文版), 2014, 23(8): 548-557.

Lu Yang, Lulu Sun, Tao Guo, Dongya Xia, Xipei Wang, Xingang Li, Wei Lu. Population pharmacokinetic of losartan and its active metabolite E-3174 in five different ethnic populations of China[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(8): 548-557.

参考文献

[1] Borghi, C.; Ertek, S. Int. Congress Ser. 2007, 1303, 129-137.

[2] Burnier, M. Circulation. 2001, 103, 904-912.

[3] Sica, D.A.; Gehr, T.W.; Ghosh, S. Clin. Pharmacokinet. 2005, 44, 797-814.

[4] Kaukonen, K.M.; Olkkola, K.T.; Neuvonen, P.J. Eur. J. Clin. Pharmacol. 1998, 53, 445-449.

[5] Johnson, J.A. Int. J. Clin. Pharmacol. Ther. 2000, 38, 53-60.

[6] Food and Drug Administration. Guidance on ethnic factors in the acceptability of foreign clinical data. Fed Regist. 1998, 63, 31790-31796.

[7] Balant, L.P.; Balant-Gorgia, E.A. Int. J. Clin. Pharmacol. Ther. 2000, 38, 47-52.

[8] Yang, L.; Guo, T.; Xia, D.Y. China Pharmacy. 2009, 20, 2509-2511.

[9] Beal, S.L.; Boeckman, A.J.; Sheiner, L.B. NONMEM: User’s Guides. San Francisco: University of California at San Francisco; 1988-1992.

[10] Comets, E.; Brendel, K.; Mentré, F. Comput. Methods Programs Biomed. 2008, 90, 154-166.

[11] Williamson, K.M.; Patterson, J.H.; McQueen, R.H.; Adams, K.F.Jr.; Pieper, J.A. Clin. Pharmacol. Ther. 1998, 63, 316-323.

[12] Soldner, A.; Spahn-Langguth, H.; Mutschler, E. J. Pharmaceut. Biomed. 1998, 16, 863-873.

[13] Yasar, U.; Tybring, G.; Hidestrand, M.; Oscarson, M.; Ingelman-Sundberg, M.; Dahl, M.L.; Eliasson, E. Drug Metab. Dispos. 2001, 29, 1051-1056.

[14] Zhao, T.M.; Zhang, G.L.; Yuan, Y.D.; Du, R.F. Acta Anthropol. Sin. 1984, 3, 166-169.

[15] Guo, T.; Sun, W.J.; Xia, D.Y.; Zhao, L.S. J. Clin. Pharm. Ther. 2010, 35,231-237.

[16] Chang, X.Y.; Guo, T.; Xia, D.Y. J. Pharm. Pharmaceut. Sci. 2009, 12, 175-180.

[17] Guo, T.; Zhao, L.S.; Xia, D.Y. J. Pharm. Pharmaceut. Sci. 2010, 13, 443-449.

[18] Guo, T.; Mao, G.F.; Xia, D.Y.; Su, X.Y.; Zhao, L.S. J. Clin. Pharm. Ther. 2011, 36, 406-411.

[19] Guo, T.; Zhao, L.S.; Wu, K.H.; Xia, D.Y.; Lu, W.; Guan, Z.; Deng, C.H. Ther. Drug Monit. 2010, 32, 189-193.

[20] Yang, L.; Guo, T.; Xia, D.Y.; Zhao, L.S. J. Clin. Pharm. Ther. 2012, 37, 226-231.

[21] Yasar, U.; Forslund-Bergengren, C.; Tybring, G.; Dorado, P.; Llerena, A.; Sjöqvist, F.; Eliasson, E.; Dahl, M.L. Clin. Pharmacol. Ther. 2002, 71, 89-98.

氯沙坦及其活性代谢物E-3174在中国不同民族健康人群中的群体药代动力学研究

Population pharmacokinetic of losartan and its active metabolite E-3174 in five different ethnic populations of China

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