Genetic influence of ABCG2, UGT1A1 and NR1I2 on dolutegravir plasma pharmacokinetics

Elliot, Emilie R, Neary, Megan, Else, Laura, Khoo, Saye ORCID: 0000-0002-2769-0967, Moyle, Graeme, Carr, Daniel F, Wang, Xinzhu, Mcclure, Myra, Boffito, Marta and Owen, Andrew ORCID: 0000-0002-9819-7651 (2020) Genetic influence of ABCG2, UGT1A1 and NR1I2 on dolutegravir plasma pharmacokinetics JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 75 (5). pp. 1259-1266. ISSN 0305-7453, 1460-2091

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Abstract

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. Methods: Paired pharmacogenetic/pharmacokinetic data from 93 subjects were analysed for association using multivariate linear regression. Results: Co-occurring UGT1∗28 and NR1I2 c.63396C>T homozygosity was associated with a 79% increase in AUC<inf>0-24</inf> (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 C<inf>max</inf> (P = 0.002) and a 39% increase in AUC<inf>0-24</inf> (P = 0.002). When analysed individually, homozygosity for the NR1I2 c.63396C>T variant alleles was associated with a 28% increase in C<inf>max</inf> (P = 0.033) and homozygosity for the ABCG2 c.421C>A variant alleles was associated with a 28% increase in C<inf>max</inf> (P = 0.047). The UGT1A1∗28 (rs8175347) poor metabolizer status (∗28/∗28; ∗28/∗37; ∗37/∗37) was individually associated with a 27% increase in AUC<inf>0-24</inf> (P = 0.020). The combination of UGT1A1∗28 poor metabolizer and UGT1A1∗6 intermediate metabolizer statuses correlated with a 43% increase in AUC<inf>0-24</inf> (P = 0.023). Conclusions: 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.

Item Type:	Article
Uncontrolled Keywords:	Humans, Oxazines, Piperazines, Pyridones, Heterocyclic Compounds, 3-Ring, Neoplasm Proteins, Polymorphism, Single Nucleotide, ATP Binding Cassette Transporter, Subfamily G, Member 2, Pregnane X Receptor, Dolutegravir
Depositing User:	Symplectic Admin
Date Deposited:	04 Mar 2020 15:40
Last Modified:	16 Jun 2026 07:20
DOI:	10.1093/jac/dkz558
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3076607
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