Influence of age and co‐medication on dolutegravir glucuronidation in paediatric patients

Abstract

Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG‐gluc). We described the dolutegravir metabolic ratio (DTG‐MR; DTG‐gluc AUC0–24h divided by DTG AUC0–24h) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS‐4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG‐MR. The overall geometric mean (CV%) DTG‐MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG‐MR (P < .001) in multiple linear regression. DTG‐MR geometric mean ratio was 1.81 (95% CI: 1.57–2.08) for children while on vs. off rifampicin. This study showed that overall DTG‐MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co‐administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data.