Influence of age and co-medication on dolutegravir glucuronidation in paediatric patients.
Tom G JacobsHylke WaalewijnLily HouldenPauline D J BollenAnnet NanduuduEsether NambiHaseena CassimAbbas LugemwaShafic MakumbiLara N MonkiewiczClare ShakeshaftAlasdair BamfordMoherndran ArcharyGodfrey MusuroEnnie ChidzivaHilda A MujuruMutsa Bwakura-DangarembiziChishala ChabalaAnna TurkovaDi M GibbMark F CottonRob AarnoutseDavid Marinus BurgerAngela ColbersPublished in: British journal of clinical pharmacology (2024)
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 AUC 0-24h ) 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.
Keyphrases
- mycobacterium tuberculosis
- contrast enhanced
- magnetic resonance
- antiretroviral therapy
- young adults
- body weight
- end stage renal disease
- emergency department
- pulmonary tuberculosis
- chronic kidney disease
- magnetic resonance imaging
- healthcare
- ejection fraction
- machine learning
- computed tomography
- hiv infected
- prognostic factors
- peritoneal dialysis