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

Tom G Jacobs; Hylke Waalewijn; Lily Houlden; Pauline D J Bollen; Annet Nanduudu; Esether Nambi; Haseena Cassim; Abbas Lugemwa; Shafic Makumbi; Lara N Monkiewicz; Clare Shakeshaft; Alasdair Bamford; Moherndran Archary; Godfrey Musuro; Ennie Chidziva; Hilda A Mujuru; Mutsa Bwakura-Dangarembizi; Chishala Chabala; Anna Turkova; Di M Gibb; Mark F Cotton; Rob Aarnoutse; David M Burger; Angela Colbers

doi:10.1111/bcp.16238

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

Br J Clin Pharmacol. 2024 Sep 3:e16238. doi: 10.1111/bcp.16238. Online ahead of print.

Authors

Tom G Jacobs¹, Hylke Waalewijn^{1

2}, Lily Houlden³, Pauline D J Bollen^{1

4}, Annet Nanduudu⁵, Esether Nambi⁵, Haseena Cassim⁶, Abbas Lugemwa⁷, Shafic Makumbi⁷, Lara N Monkiewicz³, Clare Shakeshaft³, Alasdair Bamford³, Moherndran Archary⁸, Godfrey Musuro⁹, Ennie Chidziva⁹, Hilda A Mujuru⁹, Mutsa Bwakura-Dangarembizi⁹, Chishala Chabala^{10

11}, Anna Turkova³, Di M Gibb³, Mark F Cotton¹², Rob Aarnoutse¹, David M Burger¹, Angela Colbers¹

Affiliations

¹ Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
² Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
³ Medical Research Council Clinical Trials Unit, University College London, London, UK.
⁴ Hospital Gelderse Vallei, Ede, The Netherlands.
⁵ Joint Clinical Research Centre, Kampala, Uganda.
⁶ Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
⁷ Joint Clinical Research Centre, Mbarara, Uganda.
⁸ Durban International Clinical Research Site, Durban, South Africa.
⁹ University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe.
¹⁰ Department of Paediatrics and Child Health, School of Medicine, University of Zambia, Lusaka, Zambia.
¹¹ Children's Hospital, University Teaching Hospitals, Lusaka, Zambia.
¹² Family Centre for Research with Ubuntu, Stellenbosch University, Cape Town, South Africa.

PMID: 39228168
DOI: 10.1111/bcp.16238

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 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.

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

Abstract

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