Reyes-González Stephanie, de Las Barreras Camila, Reynaldo Gledys, Rodríguez-Vera Leyanis, Vlaar Cornelis, Mejias Vilmali Lopez, Monbaliu Jean-Christophe M, Stelzer Torsten, Mangas Victor, Duconge Jorge
Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico - Medical Sciences Campus, San Juan00936,Puerto Rico, USA.
Institute of Pharmacy and Foods, University of Havana, Havana, Cuba.
Drug Metab Pers Ther. 2020 Aug 19. doi: 10.1515/dmdi-2020-0135.
Objectives The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans. Methods Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.4. The k e of warfarin given a cytochrome P450 2C9 (CYP2C9) genotype ranged from 0.0189 to 0.0075 h-1. K a and V d parameters were taken from literature. Data from 128 subjects were divided into two groups (i.e., wild-types and carriers) and statistical analyses of PK parameters were performed by unpaired t-tests. Results In the carrier group (n=64), 53 subjects were single-carriers and 11 double-carriers (i.e., *2/*2, *2/*3, *2/*5, *3/*5, and *3/*8). The mean peak concentration (Cmax) was higher for wild-type (0.36±0.12 vs. 0.32±0.14 mg/L). Likewise, the average clearance (CL) parameter was faster among non-carriers (0.22±0.03 vs. 0.17±0.05 L/h; p=0.0001), with also lower area under the curve (AUC) when compared to carriers (20.43±6.97 vs. 24.78±11.26 h mg/L; p=0.025). Statistical analysis revealed a significant difference between groups with regard to AUC and CL, but not for Cmax. This can be explained by the variation of k e across different genotypes. Conclusions The results provided useful information for warfarin dosing predictions that take into consideration important individual PK and genotyping data.
目的 华法林剂量的个体间差异与基因多态性有关。本研究旨在进行基因型驱动的药代动力学（PK）模拟，以预测波多黎各人的华法林水平。方法 使用WinNonlin®v6.4通过单室模型对每个个体数据集进行分析。根据细胞色素P450 2C9（CYP2C9）基因型，华法林的消除速率常数（ke）范围为0.0189至0.0075 h-1。吸收速率常数（Ka）和分布容积（Vd）参数取自文献。将128名受试者的数据分为两组（即野生型和携带者），并通过非配对t检验对PK参数进行统计分析。结果 在携带者组（n = 64）中，53名受试者为单携带者，11名受试者为双携带者（即*2/*2、*2/*3、*2/*5、*3/5和3/*8）。野生型的平均峰浓度（Cmax）更高（0.36±0.12 vs. 0.32±0.14 mg/L）。同样，非携带者的平均清除率（CL）参数更快（0.22±0.03 vs. 0.17±0.05 L/h；p = 0.0001），与携带者相比，曲线下面积（AUC）也更低（20.43±6.97 vs. 24.78±11.26 h mg/L；p = 0.025）。统计分析显示，两组在AUC和CL方面存在显著差异，但Cmax无显著差异。这可以通过不同基因型的ke变化来解释。结论 这些结果为考虑重要个体PK和基因分型数据的华法林剂量预测提供了有用信息。
