Elliot Emilie R, Neary Megan, Else Laura, Khoo Saye, Moyle Graeme, Carr Daniel F, Wang Xinzhu, Mcclure Myra, Boffito Marta, Owen Andrew
Chelsea and Westminster Hospital, London, UK.
University of Liverpool, Liverpool, UK.
J Antimicrob Chemother. 2020 May 1;75(5):1259-1266. doi: 10.1093/jac/dkz558.
Dolutegravir has replaced efavirenz as first-line treatment in universal HIV guidelines. We sought to ascertain the contributory effect of SNPs in four key genes linked to dolutegravir disposition (UGT1A1, ABCG2, CYP3A and NR1I2) on plasma dolutegravir pharmacokinetics.
Paired pharmacogenetic/pharmacokinetic data from 93 subjects were analysed for association using multivariate linear regression.
Co-occurring UGT128 and NR1I2 c.63396C>T homozygosity was associated with a 79% increase in AUC0-24 (P = 0.001; 27% if analysed individually), whilst combined ABCG2 c.421C>A and NR1I2 c.63396C>T variants were associated with a 43% increase in Cmax (P = 0.002) and a 39% increase in AUC0-24 (P = 0.002). When analysed individually, homozygosity for the NR1I2 c.63396C>T variant alleles was associated with a 28% increase in Cmax (P = 0.033) and homozygosity for the ABCG2 c.421C>A variant alleles was associated with a 28% increase in Cmax (P = 0.047). The UGT1A128 (rs8175347) poor metabolizer status (*28/*28; *28/*37; 37/37) was individually associated with a 27% increase in AUC0-24 (P = 0.020). The combination of UGT1A128 poor metabolizer and UGT1A16 intermediate metabolizer statuses correlated with a 43% increase in AUC0-24 (P = 0.023).
This study showed a pharmacogenetic association between dolutegravir pharmacokinetics and variants in the ABCG2, UGT1A1 and NR1I2 genes, particularly when combined. Further research is warranted to confirm these associations in population-specific studies and to investigate their putative relationship with dolutegravir pharmacodynamics.
在通用的HIV治疗指南中，多替拉韦已取代依非韦伦作为一线治疗药物。我们试图确定与多替拉韦处置相关的四个关键基因（UGT1A1、ABCG2、CYP3A和NR1I2）中的单核苷酸多态性（SNP）对血浆多替拉韦药代动力学的影响。
使用多变量线性回归分析93名受试者的配对药物遗传学/药代动力学数据，以确定其关联性。
UGT128和NR1I2基因c.63396C>T位点的纯合性共同出现与AUC0-24增加79%相关（P = 0.001；单独分析时增加27%），而ABCG2基因c.421C>A和NR1I2基因c.63396C>T变异的组合与Cmax增加43%（P = 0.002）和AUC0-24增加39%（P = 0.002）相关。单独分析时，NR1I2基因c.63396C>T变异等位基因的纯合性与Cmax增加28%相关（P = 0.033），ABCG2基因c.421C>A变异等位基因的纯合性与Cmax增加28%相关（P = 0.047）。UGT1A128（rs8175347）慢代谢状态（*28/*28；*28/*37；37/37）单独与AUC0-24增加27%相关（P = 0.020）。UGT1A128慢代谢状态与UGT1A16中间代谢状态的组合与AUC0-24增加43%相关（P = 0.023）。
本研究显示多替拉韦药代动力学与ABCG2、UGT1A1和NR1I2基因变异之间存在药物遗传学关联，尤其是基因变异组合时。有必要开展进一步研究，在特定人群研究中证实这些关联，并探究它们与多替拉韦药效学之间的假定关系。
