Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial

BACKGROUND: Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment option...

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Autores principales: Bevers, Lisanne A H, Waalewijn, Hylke, Szubert, Alexander J, Chabala, Chishala, Bwakura-Dangarembizi, Mutsa, Makumbi, Shafic, Nangiya, Joan, Mumbiro, Vivian, Mulenga, Veronica, Musiime, Victor, Burger, David M, Gibb, Diana M, Colbers, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10640690/
https://www.ncbi.nlm.nih.gov/pubmed/37280040
http://dx.doi.org/10.1093/cid/ciad346
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author Bevers, Lisanne A H
Waalewijn, Hylke
Szubert, Alexander J
Chabala, Chishala
Bwakura-Dangarembizi, Mutsa
Makumbi, Shafic
Nangiya, Joan
Mumbiro, Vivian
Mulenga, Veronica
Musiime, Victor
Burger, David M
Gibb, Diana M
Colbers, Angela
author_facet Bevers, Lisanne A H
Waalewijn, Hylke
Szubert, Alexander J
Chabala, Chishala
Bwakura-Dangarembizi, Mutsa
Makumbi, Shafic
Nangiya, Joan
Mumbiro, Vivian
Mulenga, Veronica
Musiime, Victor
Burger, David M
Gibb, Diana M
Colbers, Angela
author_sort Bevers, Lisanne A H
collection PubMed
description BACKGROUND: Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14–19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (C(trough)) was defined as 0.32 mg/L. RESULTS: Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration–time curve over the dosing interval (AUC(0-24h)) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC(0-24h) in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) C(trough) was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references. Clinical Trials Registration.ISRCTN22964075.
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spelling pubmed-106406902023-11-14 Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial Bevers, Lisanne A H Waalewijn, Hylke Szubert, Alexander J Chabala, Chishala Bwakura-Dangarembizi, Mutsa Makumbi, Shafic Nangiya, Joan Mumbiro, Vivian Mulenga, Veronica Musiime, Victor Burger, David M Gibb, Diana M Colbers, Angela Clin Infect Dis Major Article BACKGROUND: Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14–19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (C(trough)) was defined as 0.32 mg/L. RESULTS: Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration–time curve over the dosing interval (AUC(0-24h)) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC(0-24h) in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) C(trough) was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references. Clinical Trials Registration.ISRCTN22964075. Oxford University Press 2023-06-06 /pmc/articles/PMC10640690/ /pubmed/37280040 http://dx.doi.org/10.1093/cid/ciad346 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Major Article
Bevers, Lisanne A H
Waalewijn, Hylke
Szubert, Alexander J
Chabala, Chishala
Bwakura-Dangarembizi, Mutsa
Makumbi, Shafic
Nangiya, Joan
Mumbiro, Vivian
Mulenga, Veronica
Musiime, Victor
Burger, David M
Gibb, Diana M
Colbers, Angela
Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial
title Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial
title_full Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial
title_fullStr Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial
title_full_unstemmed Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial
title_short Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial
title_sort pharmacokinetic data of dolutegravir in second-line treatment of children with human immunodeficiency virus: results from the chapas4 trial
topic Major Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10640690/
https://www.ncbi.nlm.nih.gov/pubmed/37280040
http://dx.doi.org/10.1093/cid/ciad346
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