Population pharmacokinetics of ethambutol in African children : a pooled analysis
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
OBJECTIVES: Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population.
METHODS: We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3-12.6) years and 9.6 (3.9-34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92%).
RESULTS: Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2 months after birth and 99% by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax = 0.882 (0.669-1.28) versus 1.66 (1.21-2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16 years or older.
CONCLUSIONS: To obtain exposure within the 2-6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:77 |
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| Enthalten in: |
The Journal of antimicrobial chemotherapy - 77(2022), 7 vom: 29. Juni, Seite 1949-1959 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tikiso, Tjokosela [VerfasserIn] |
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| Links: |
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| Themen: |
2494G1JF75 |
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| Anmerkungen: |
Date Completed 01.07.2022 Date Revised 14.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/jac/dkac127 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM339954841 |
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| 245 | 1 | 0 | |a Population pharmacokinetics of ethambutol in African children |b a pooled analysis |
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| 500 | |a Date Completed 01.07.2022 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a OBJECTIVES: Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population | ||
| 520 | |a METHODS: We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3-12.6) years and 9.6 (3.9-34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92%) | ||
| 520 | |a RESULTS: Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2 months after birth and 99% by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax = 0.882 (0.669-1.28) versus 1.66 (1.21-2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16 years or older | ||
| 520 | |a CONCLUSIONS: To obtain exposure within the 2-6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Meta-Analysis | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Lopinavir |2 NLM | |
| 650 | 7 | |a 2494G1JF75 |2 NLM | |
| 650 | 7 | |a Ethambutol |2 NLM | |
| 650 | 7 | |a 8G167061QZ |2 NLM | |
| 650 | 7 | |a Ritonavir |2 NLM | |
| 650 | 7 | |a O3J8G9O825 |2 NLM | |
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| 700 | 1 | |a Abdelwahab, Mahmoud Tareq |e verfasserin |4 aut | |
| 700 | 1 | |a Bekker, Adrie |e verfasserin |4 aut | |
| 700 | 1 | |a Hesseling, Anneke |e verfasserin |4 aut | |
| 700 | 1 | |a Chabala, Chishala |e verfasserin |4 aut | |
| 700 | 1 | |a Davies, Geraint |e verfasserin |4 aut | |
| 700 | 1 | |a Zar, Heather J |e verfasserin |4 aut | |
| 700 | 1 | |a Rabie, Helena |e verfasserin |4 aut | |
| 700 | 1 | |a Andrieux-Meyer, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Janice |e verfasserin |4 aut | |
| 700 | 1 | |a Wiesner, Lubbe |e verfasserin |4 aut | |
| 700 | 1 | |a Cotton, Mark F |e verfasserin |4 aut | |
| 700 | 1 | |a Denti, Paolo |e verfasserin |4 aut | |
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