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

OBJECTIVES

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 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).

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.