Influence of age and co‐medication on dolutegravir glucuronidation in paediatric patients-Reference-Cited by-同舟云学术

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

Published:2024-09-03 Issue: Volume: Page:
ISSN:0306-5251
Container-title:British Journal of Clinical Pharmacology
language:en
Short-container-title:Brit J Clinical Pharma

Author:

Jacobs Tom G.¹^ORCID,Waalewijn Hylke¹²,Houlden Lily³,Bollen Pauline D. J.¹⁴,Nanduudu Annet⁵,Nambi Esether⁵,Cassim Haseena⁶,Lugemwa Abbas⁷,Makumbi Shafic⁷,Monkiewicz Lara N.³,Shakeshaft Clare³,Bamford Alasdair³,Archary Moherndran⁸^ORCID,Musuro Godfrey⁹,Chidziva Ennie⁹,Mujuru Hilda A.⁹,Bwakura‐Dangarembizi Mutsa⁹,Chabala Chishala¹⁰¹¹,Turkova Anna³,Gibb Di M.³,Cotton Mark F.¹²,Aarnoutse Rob¹,Burger David M.¹^ORCID,Colbers Angela¹

Affiliation:

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

Abstract

AbstractDolutegravir (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.

Funder

European and Developing Countries Clinical Trials Partnership

ViiV Healthcare

Medical Research Council

Janssen Pharmaceutica

Gilead Sciences

Publisher

Wiley

Link

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.16238

Reference24 articles.

1. UNAIDS.UNAIDS data 2021.2022[cited 2022 09 August 2022]. Available from:https://www.unaids.org/sites/default/files/media_asset/JC3032_AIDS_Data_book_2021_En.pdf

2. Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children

3. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV.Guidelines for the use of antiretroviral agents in pediatric HIV infection.2022[cited 2022 09 August 2022]. Available from:https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv

4. World Health Organization.Consolidated guidelines on HIV prevention testing treatment service delivery and monitoring: recommendations for a public health approach.2021. [2021 01/05/2023]; Available from:https://www.who.int/publications/i/item/9789240031593