Tsamandouras Nikolaos, Guo Yingying, Wendling Thierry, Hall Stephen, Galetin Aleksandra, Aarons Leon
aManchester Pharmacy School, Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK bEli Lilly and Company, Indianapolis, Indiana, USA.
Pharmacogenet Genomics. 2017 Jan;27(1):27-38. doi: 10.1097/FPC.0000000000000252.
Ethnicity plays a modulating role in atorvastatin pharmacokinetics (PK), with Asian patients reported to have higher exposure compared with Caucasians. Therefore, it is difficult to safely extrapolate atorvastatin PK data and models across ethnic groups. This work aims to develop a population PK model for atorvastatin and its pharmacologically active metabolites specifically for the Japanese population. Subsequently, it aimed to identify genetic polymorphisms affecting atorvastatin PK in this population.
Atorvastatin acid (ATA) and ortho-hydroxy-atorvastatin acid (o-OH-ATA) plasma concentrations, clinical/demographic characteristics and genotypes for 18 (3, 3, 1, 1, 7, 2 and 1 in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes, respectively) genetic polymorphisms were collected from 27 Japanese individuals (taking 10 mg atorvastatin once daily) and analysed using a population PK modelling approach.
The population PK model developed (one-compartment for ATA linked through metabolite formation to an additional compartment describing the disposition of o-OH-ATA) accurately described the observed data and the associated population variability. Our analysis suggested that patients carrying one variant allele for the rs2622604 polymorphism (ABCG2) show a 55% (95% confidence interval: 16-131%) increase in atorvastatin oral bioavailability relative to the value in individuals without the variant allele.
The current work reports the identification in the Japanese population of a BCRP polymorphism, not previously associated with the PK of any statin, that markedly increases ATA and o-OH-ATA exposure. The model developed may be of clinical importance to guide dosing recommendations tailored specifically for the Japanese.
种族在阿托伐他汀药代动力学（PK）中起调节作用，据报道亚洲患者与白种人相比有更高的药物暴露量。因此，很难在不同种族间安全地外推阿托伐他汀的PK数据和模型。本研究旨在为日本人群开发一个针对阿托伐他汀及其药理活性代谢物的群体PK模型。随后，旨在确定影响该人群中阿托伐他汀PK的基因多态性。
收集了27名日本个体（每日一次服用10mg阿托伐他汀）的阿托伐他汀酸（ATA）和邻羟基阿托伐他汀酸（o-OH-ATA）血浆浓度、临床/人口统计学特征以及18种（分别在ABCB1、ABCG2、CYP3A4、CYP3A5、SLCO1B1、SLCO2B1和PPARA基因中各有3、3、1、1、7、2和1种）基因多态性的基因型，并采用群体PK建模方法进行分析。
所开发的群体PK模型（ATA的一室模型通过代谢物形成与描述o-OH-ATA处置的另一个室相连）准确描述了观察到的数据及相关的群体变异性。我们的分析表明，携带rs2622604多态性（ABCG2）一个变异等位基因的患者相对于没有该变异等位基因的个体，阿托伐他汀口服生物利用度增加55%（95%置信区间：16-131%）。
当前研究报告了在日本人群中鉴定出一种此前未与任何他汀类药物PK相关的BCRP多态性，该多态性显著增加了ATA和o-OH-ATA的暴露量。所开发的模型对于指导专门针对日本人的给药建议可能具有临床重要性。
