Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children

Abstract

Background: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677) and UGT1A1 (rs5839491) on dolutegravir PK was examined. Methods: Children defined by age and administered dolutegravir formulation had AUC24 at steady state, Cmax and C24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. Results: The 59 children studied had a median age of 4.6 years, log10 plasma HIV RNA of 4.79 (copies/mm3) and CD4+ lymphocyte count 1,041 cells/mm3; 51% were female. For ABCG2, participants with >1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex, (-15.7, 95% CI: [-32.0, 0.6], p = 0.06) and log10Cmax adjusted mean difference (-0.15 (95% CI: [-0.25, -0.05], p = 0.003). Participants with >1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1, 25.0], p = 0.07). For UGT1A1, poor metabolizers had non-significant higher concentrations (adjusted log10Cmax mean difference 11.8; 95% CI: [-12.3, 36.0], p = 0.34) and lower mean log10 adjusted oral clearance -0.13 L/hr (95% CI: [-0.3, 0.06], p = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA or CD4+ cell counts. Conclusions: Dolutegravir AUC24 for genetic variants in ABCG2, NR1l2 and UGT1A1 varied from -25% to +33%.These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.