Population pharmacokinetics of ethambutol in African children: a pooled analysis

Tikiso, Tjokosela, McIlleron, Helen, Abdelwahab, Mahmoud Tareq, Bekker, Adrie, Hesseling, Anneke, Chabala, Chishala, Davies, Geraint ORCID: 0000-0002-3819-490X, Zar, Heather J, Rabie, Helena, Andrieux-Meyer, Isabelle
et al (show 4 more authors) (2022) Population pharmacokinetics of ethambutol in African children: a pooled analysis. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 77 (7). pp. 1949-1959.

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<h4>Objectives</h4>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.<h4>Methods</h4>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%).<h4>Results</h4>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.<h4>Conclusions</h4>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.

Item Type: Article
Uncontrolled Keywords: Humans, HIV Infections, Ethambutol, Ritonavir, Antitubercular Agents, Anti-HIV Agents, Child, Child, Preschool, Infant, Newborn, Lopinavir
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User: Symplectic Admin
Date Deposited: 02 Feb 2024 10:31
Last Modified: 02 Feb 2024 10:31
DOI: 10.1093/jac/dkac127
Open Access URL: https://doi.org/10.1093/jac/dkac127
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3178285