1. Influence of age and co-medication on dolutegravir glucuronidation in paediatric patients.
- Author
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Jacobs TG, Waalewijn H, Houlden L, Bollen PDJ, Nanduudu A, Nambi E, Cassim H, Lugemwa A, Makumbi S, Monkiewicz LN, Shakeshaft C, Bamford A, Archary M, Musuro G, Chidziva E, Mujuru HA, Bwakura-Dangarembizi M, Chabala C, Turkova A, Gibb DM, Cotton MF, Aarnoutse R, Burger DM, and Colbers A
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Age Factors, Area Under Curve, Reverse Transcriptase Inhibitors pharmacokinetics, Reverse Transcriptase Inhibitors therapeutic use, Randomized Controlled Trials as Topic, Drug Interactions, Glucuronides metabolism, Heterocyclic Compounds, 3-Ring pharmacokinetics, Heterocyclic Compounds, 3-Ring therapeutic use, Heterocyclic Compounds, 3-Ring administration & dosage, HIV Infections drug therapy, HIV Integrase Inhibitors pharmacokinetics, HIV Integrase Inhibitors therapeutic use, HIV Integrase Inhibitors administration & dosage, Oxazines pharmacokinetics, Piperazines, Pyridones pharmacokinetics, Rifampin therapeutic use, Rifampin pharmacology, Rifampin pharmacokinetics, Rifampin administration & dosage
- 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 AUC
0-24h 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., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2024
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