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

Br J Clin Pharmacol. 2024 Nov;90(11):2947-2952. doi: 10.1111/bcp.16238. Epub 2024 Sep 3.

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.

Keywords: HIV; UGT1A1; children; dolutegravir; drug–drug interaction; glucuronidation; pharmacokinetics.

MeSH terms

  • Adolescent
  • Age Factors
  • Area Under Curve
  • Child
  • Child, Preschool
  • Drug Interactions*
  • Female
  • Glucuronides* / metabolism
  • HIV Infections* / drug therapy
  • HIV Integrase Inhibitors* / administration & dosage
  • HIV Integrase Inhibitors* / pharmacokinetics
  • HIV Integrase Inhibitors* / therapeutic use
  • Heterocyclic Compounds, 3-Ring* / administration & dosage
  • Heterocyclic Compounds, 3-Ring* / pharmacokinetics
  • Heterocyclic Compounds, 3-Ring* / therapeutic use
  • Humans
  • Infant
  • Male
  • Oxazines* / pharmacokinetics
  • Piperazines*
  • Pyridones* / pharmacokinetics
  • Randomized Controlled Trials as Topic
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Rifampin* / administration & dosage
  • Rifampin* / pharmacokinetics
  • Rifampin* / pharmacology
  • Rifampin* / therapeutic use

Substances

  • dolutegravir
  • Glucuronides
  • Heterocyclic Compounds, 3-Ring
  • HIV Integrase Inhibitors
  • Oxazines
  • Piperazines
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • Rifampin