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First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial
BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3–15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10506774/ https://www.ncbi.nlm.nih.gov/pubmed/37315296 http://dx.doi.org/10.1093/cid/ciad267 |
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author | Waalewijn, Hylke Szubert, Alexander J Wasmann, Roeland E Wiesner, Lubbe Chabala, Chishala Bwakura-Dangarembizi, Mutsa Makumbi, Shafic Nangiya, Joan Mumbiro, Vivian Mulenga, Veronica Musiime, Victor Monkiewicz, Lara N Griffiths, Anna L Bamford, Alasdair Doerholt, Katja Denti, Paolo Burger, David M Gibb, Diana M McIlleron, Helen M Colbers, Angela |
author_facet | Waalewijn, Hylke Szubert, Alexander J Wasmann, Roeland E Wiesner, Lubbe Chabala, Chishala Bwakura-Dangarembizi, Mutsa Makumbi, Shafic Nangiya, Joan Mumbiro, Vivian Mulenga, Veronica Musiime, Victor Monkiewicz, Lara N Griffiths, Anna L Bamford, Alasdair Doerholt, Katja Denti, Paolo Burger, David M Gibb, Diana M McIlleron, Helen M Colbers, Angela |
author_sort | Waalewijn, Hylke |
collection | PubMed |
description | BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3–15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)–recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8–9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration–time curve (AUC) and the maximum concentration (C(max)) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUC(last) when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUC(last) increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUC(tau) and C(max) remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075. |
format | Online Article Text |
id | pubmed-10506774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-105067742023-09-19 First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial Waalewijn, Hylke Szubert, Alexander J Wasmann, Roeland E Wiesner, Lubbe Chabala, Chishala Bwakura-Dangarembizi, Mutsa Makumbi, Shafic Nangiya, Joan Mumbiro, Vivian Mulenga, Veronica Musiime, Victor Monkiewicz, Lara N Griffiths, Anna L Bamford, Alasdair Doerholt, Katja Denti, Paolo Burger, David M Gibb, Diana M McIlleron, Helen M Colbers, Angela Clin Infect Dis Major Article BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3–15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)–recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8–9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration–time curve (AUC) and the maximum concentration (C(max)) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUC(last) when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUC(last) increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUC(tau) and C(max) remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075. Oxford University Press 2023-05-09 /pmc/articles/PMC10506774/ /pubmed/37315296 http://dx.doi.org/10.1093/cid/ciad267 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Major Article Waalewijn, Hylke Szubert, Alexander J Wasmann, Roeland E Wiesner, Lubbe Chabala, Chishala Bwakura-Dangarembizi, Mutsa Makumbi, Shafic Nangiya, Joan Mumbiro, Vivian Mulenga, Veronica Musiime, Victor Monkiewicz, Lara N Griffiths, Anna L Bamford, Alasdair Doerholt, Katja Denti, Paolo Burger, David M Gibb, Diana M McIlleron, Helen M Colbers, Angela First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial |
title | First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial |
title_full | First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial |
title_fullStr | First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial |
title_full_unstemmed | First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial |
title_short | First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial |
title_sort | first pharmacokinetic data of tenofovir alafenamide fumarate and tenofovir with dolutegravir or boosted protease inhibitors in african children: a substudy of the chapas-4 trial |
topic | Major Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10506774/ https://www.ncbi.nlm.nih.gov/pubmed/37315296 http://dx.doi.org/10.1093/cid/ciad267 |
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