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

doi:10.5246/jcps.2014.08.071

Journal of Chinese Pharmaceutical Sciences ›› 2014, Vol. 23 ›› Issue (8): 548-557.DOI: 10.5246/jcps.2014.08.071

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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).

Abstract

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

CLC Number:

R969

Supporting:

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.

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

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