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

Autor: Jacobs TG; Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands., Waalewijn H; Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Houlden L; Medical Research Council Clinical Trials Unit, University College London, London, UK., Bollen PDJ; Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.; Hospital Gelderse Vallei, Ede, The Netherlands., Nanduudu A; Joint Clinical Research Centre, Kampala, Uganda., Nambi E; Joint Clinical Research Centre, Kampala, Uganda., Cassim H; Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa., Lugemwa A; Joint Clinical Research Centre, Mbarara, Uganda., Makumbi S; Joint Clinical Research Centre, Mbarara, Uganda., Monkiewicz LN; Medical Research Council Clinical Trials Unit, University College London, London, UK., Shakeshaft C; Medical Research Council Clinical Trials Unit, University College London, London, UK., Bamford A; Medical Research Council Clinical Trials Unit, University College London, London, UK., Archary M; Durban International Clinical Research Site, Durban, South Africa., Musuro G; University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe., Chidziva E; University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe., Mujuru HA; University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe., Bwakura-Dangarembizi M; University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe., Chabala C; Department of Paediatrics and Child Health, School of Medicine, University of Zambia, Lusaka, Zambia.; Children's Hospital, University Teaching Hospitals, Lusaka, Zambia., Turkova A; Medical Research Council Clinical Trials Unit, University College London, London, UK., Gibb DM; Medical Research Council Clinical Trials Unit, University College London, London, UK., Cotton MF; Family Centre for Research with Ubuntu, Stellenbosch University, Cape Town, South Africa., Aarnoutse R; Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands., Burger DM; Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands., Colbers A; Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2024 Nov; Vol. 90 (11), pp. 2947-2952. Date of Electronic Publication: 2024 Sep 03.
DOI: 10.1111/bcp.16238
Abstrakt: 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.
(© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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