Kubo K, Ohara M, Tachikawa M, Cavallari L H, Lee M T M, Wen M S, Scordo M G, Nutescu E A, Perera M A, Miyajima A, Kaneko N, Pengo V, Padrini R, Chen Y T, Takahashi H
Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
Pharmacogenomics J. 2017 Dec;17(6):494-500. doi: 10.1038/tpj.2016.57. Epub 2016 Aug 9.
Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9*2,*3 and 8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C91/*1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.
我们运用群体药代动力学分析（PPK），试图确定S-华法林清除率（CL(S)）的预测因素，并阐明378名非裔美国人、亚洲人和白人患者群体中S-华法林药代动力学的种族差异。CL(S)的显著预测因素包括临床因素（年龄、体重和性别）、基因型因素（CYP2C92、3和8）以及非裔美国人种族，非裔美国人的CL(S)中位数比亚洲人和白人低30%（分别为170与243和250 ml/h，P<0.01）。使用PPK估算值模拟的基于基因型的给药算法后的血浆S-华法林（Cp(S)）时间进程显示，携带CYP2C91/*1和任何一种VKORC1基因型的非裔美国人在稳态时的平均Cp(S)比亚洲人和白人高1.5至1.8倍。这些结果表明，华法林给药算法应在各相应种族群体中进行评估。有必要对大量非裔美国人队列进行进一步研究以证实目前的发现。
