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
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America..
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 (Cmax) 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 AUClast 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 AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:77 |
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| Enthalten in: |
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America - 77(2023), 6 vom: 18. Sept., Seite 875-882 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Waalewijn, Hylke [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.09.2023 Date Revised 13.03.2024 published: Print ISRCTN: ISRCTN22964075 Citation Status MEDLINE |
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| doi: |
10.1093/cid/ciad267 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358169305 |
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| 100 | 1 | |a Waalewijn, Hylke |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children |b A Substudy of the CHAPAS-4 Trial |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 20.09.2023 | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ISRCTN: ISRCTN22964075 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. | ||
| 520 | |a BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial | ||
| 520 | |a 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 (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults | ||
| 520 | |a RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast 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 AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors | ||
| 520 | |a 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 | ||
| 520 | |a CLINICAL TRIALS REGISTRATION: ISRCTN22964075 | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a TAF | |
| 650 | 4 | |a children | |
| 650 | 4 | |a drug interaction | |
| 650 | 4 | |a pharmacokinetics | |
| 650 | 7 | |a Ritonavir |2 NLM | |
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| 650 | 7 | |a Darunavir |2 NLM | |
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| 650 | 7 | |a Tenofovir |2 NLM | |
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| 650 | 7 | |a Emtricitabine |2 NLM | |
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| 650 | 7 | |a Fumarates |2 NLM | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 700 | 1 | |a Szubert, Alexander J |e verfasserin |4 aut | |
| 700 | 1 | |a Wasmann, Roeland E |e verfasserin |4 aut | |
| 700 | 1 | |a Wiesner, Lubbe |e verfasserin |4 aut | |
| 700 | 1 | |a Chabala, Chishala |e verfasserin |4 aut | |
| 700 | 1 | |a Bwakura-Dangarembizi, Mutsa |e verfasserin |4 aut | |
| 700 | 1 | |a Makumbi, Shafic |e verfasserin |4 aut | |
| 700 | 1 | |a Nangiya, Joan |e verfasserin |4 aut | |
| 700 | 1 | |a Mumbiro, Vivian |e verfasserin |4 aut | |
| 700 | 1 | |a Mulenga, Veronica |e verfasserin |4 aut | |
| 700 | 1 | |a Musiime, Victor |e verfasserin |4 aut | |
| 700 | 1 | |a Monkiewicz, Lara N |e verfasserin |4 aut | |
| 700 | 1 | |a Griffiths, Anna L |e verfasserin |4 aut | |
| 700 | 1 | |a Bamford, Alasdair |e verfasserin |4 aut | |
| 700 | 1 | |a Doerholt, Katja |e verfasserin |4 aut | |
| 700 | 1 | |a Denti, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Burger, David M |e verfasserin |4 aut | |
| 700 | 1 | |a Gibb, Diana M |e verfasserin |4 aut | |
| 700 | 1 | |a McIlleron, Helen M |e verfasserin |4 aut | |
| 700 | 1 | |a Colbers, Angela |e verfasserin |4 aut | |
| 700 | 0 | |a Children with HIV in Africa – Pharmacokinetics and Acceptability of Simple second-line antiretroviral regimens (CHAPAS-4) Trial Team |e verfasserin |4 aut | |
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