No age-related difference in dolutegravir metabolic glucuronidation ratio in children between 3 months and 18 years old in the ODYSSEY trial


BACKGROUND: ODYSSEY and IMPAACT-P1093 found lower and more variable dolutegravir (DTG) exposure in children compared to adults based on mg/kg dose. Investigating the main metabolic pathway (UGT1A1) for DTG could help to explain these findings. Estimates of DTG glucuronide/DTG molar metabolic ratio (DTG-MR) are 0.05-0.08 in adults but this has not been studied in children.
METHODS: A subset of children was selected from PK substudies within the ODYSSEY trial, including all children aged <2 years and a random sample of older children receiving DTG film-coated tablets (FCT; >=20kg) or dispersible tablets (DT; 3-<25kg). DTG and DTG-glucuronide concentrations were measured with a validated UPLC-MS/MS assay and geometric mean (GM) DTG-MR was determined using 3 plasma samples per PK curve (t=2, 6 and 24h). We assessed correlation between DTG-MR and DTG clearance in children, as clearance adjusted for formulation is independent of DTG dose, and it is associated with DTG exposure. Pearson's correlation coefficient was used on log-transformed data to assess the relationships between DTG-MR and DTG clearance/kg (corrected for higher bioavailability of DT), and DTG-MR and age (not log-transformed).
RESULTS: In total, 37 children (age 3 months ' 18 years) were included in this study. There was positive relationship between DTG-MR and DTG clearance/kg in children (r(37)=0.64, p<.001) (Figure). No association was found between DTG-MR and age (r(37)=-0.12, p=0.50). GM(CV%) DTG-MR in children was 0.051(66%), in line with adult values.
CONCLUSIONS: Intersubject variability in DTG-MR was high in children and as the ratio correlates with clearance, this may explain high variability of DTG exposure between children. DTG-MR was similar to adult values and did not change with age, hence increased glucuronidation does not appear to explain the relatively low DTG exposure observed in children aged >3 months. Further studies are needed to assess the role other factors contributing to differences in DTG exposure in children.