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Population pharmacokinetics of ethambutol in African children: a pooled analysis

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...

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Detalles Bibliográficos
Autores principales: Tikiso, Tjokosela, McIlleron, Helen, Abdelwahab, Mahmoud Tareq, Bekker, Adrie, Hesseling, Anneke, Chabala, Chishala, Davies, Geraint, Zar, Heather J, Rabie, Helena, Andrieux-Meyer, Isabelle, Lee, Janice, Wiesner, Lubbe, Cotton, Mark F, Denti, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9633720/
https://www.ncbi.nlm.nih.gov/pubmed/35466379
http://dx.doi.org/10.1093/jac/dkac127
Descripción
Sumario: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 C(max) = 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 C(max), 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.