UGT1A1 和 SLC22A6 多态性对艾滋病毒感染成人中拉替拉韦群体药代动力学和药效学的影响：NEAT001/ANRS143 子研究

IF 2.9 3区医学 Q2 GENETICS & HEREDITY

Pharmacogenomics Journal Pub Date : 2022-10-20 DOI:10.1038/s41397-022-00293-5

Rohan Gurjar, Laura Dickinson, Daniel Carr, Wolfgang Stöhr, Stefano Bonora, Andrew Owen, Antonio D’Avolio, Adam Cursley, Nathalie De Castro, Gerd Fätkenheuer, Linos Vandekerckhove, Giovanni Di Perri, Anton Pozniak, Christine Schwimmer, François Raffi, Marta Boffito, the NEAT001/ANRS143 Study Group

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引用次数: 0

摘要

利用NEAT001/ARNS143研究的浓度-时间数据（第4周和第24周的单个样本），我们使用非线性混合效应模型（NONMEM v.7.3；来自349名患者的602个样本）确定了雷特格韦药代动力学参数，并研究了人口统计学和SNPs（SLC22A6和UGT1A1）对雷特格韦药代动力学和药效学的影响。人口统计学和 SNPs 不影响雷特格韦药代动力学，也未观察到显著的药代动力学/药效学关系。在第 96 周，UGT1A1*28/*28 与较低的病毒学失败率相关（p = 0.012），即使在调整了基线 CD4 细胞数（p = 0.048）后也是如此，但在调整了基线 HIV-1 病毒载量（p = 0.082）或两者（p = 0.089）后则不相关。据我们所知，这是第一项评估 SNPs 对雷特格韦药效学影响的研究。缺乏药代动力学/药效学关系可能是拉替拉韦在患者之间和患者内部具有高变异性这一特性的假象，同时也表明单个时间点采样计划不足以全面评估 SNPs 对拉替拉韦药代动力学的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study

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Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study

Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir’s characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.

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来源期刊

Pharmacogenomics Journal 医学-药学

CiteScore

7.20

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The Pharmacogenomics Journal is a print and electronic journal, which is dedicated to the rapid publication of original research on pharmacogenomics and its clinical applications. Key areas of coverage include: Personalized medicine Effects of genetic variability on drug toxicity and efficacy Identification and functional characterization of polymorphisms relevant to drug action Pharmacodynamic and pharmacokinetic variations and drug efficacy Integration of new developments in the genome project and proteomics into clinical medicine, pharmacology, and therapeutics Clinical applications of genomic science Identification of novel genomic targets for drug development Potential benefits of pharmacogenomics.