Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol



Mlotha, R, Waterhouse, D, Dzinjalamala, F, Ardrey, A, Molyneux, E, Davies, G ORCID: 0000-0002-3819-490X and Ward, S
(2015) Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol. The Journal of Antimicrobial Chemotherapy, 70 (6). pp. 1798-1803.

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Abstract

Background Current guidelines for dosing of anti-TB drugs in children advocate higher doses for rifampicin and isoniazid despite limited availability of paediatric data on the pharmacokinetics of these drugs, especially from Africa, where the burden of childhood disease remains high. Methods Thirty children aged 6 months to 15 years underwent intensive pharmacokinetic sampling for first-line anti-TB drugs at Queen Elizabeth Central Hospital, Blantyre, Malawi. Rifampicin, isoniazid, pyrazinamide and ethambutol were dosed at 10, 5, 25 and 20 mg/kg, respectively. Plasma drug concentrations were determined using sensitive, validated bioanalytical methods and summary pharmacokinetic parameters were estimated using non-compartmental analysis. Results The median (IQR) Cmax was 2.90 (2.08–3.43), 3.37 (2.55–4.59), 34.60 (32.30–40.90) and 1.20 (0.85–1.68) mg/L while the median (IQR) AUC0–∞ was 16.92 (11.10–22.74), 11.48 (7.35–18.93), 333.50 (279.50–487.2) and 8.65 (5.96–11.47) mg·h/L for rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. For all drugs, pharmacokinetic parameters relating to drug absorption and exposure were lower than those published for adults, though similar to existing paediatric data from sub-Saharan Africa. Weight and/or dose predicted at least one measure of exposure for all drugs. Age-related decreases in CL/F for rifampicin and pyrazinamide and a biphasic elimination pattern of isoniazid were observed. Predicted AUC0–∞ for rifampicin dosed at 15 mg/kg was comparable to that of adults while the dose required to achieve ethambutol exposure similar to that in adults was 55 mg/kg or higher. Conclusions These data support recently revised WHO recommendations for dosing of anti-TB drugs in children, but dosing of ethambutol in children also appears inadequate by comparison with adult pharmacokinetic data.

Item Type: Article
Uncontrolled Keywords: tuberculosis, paediatrics, PK, Africa
Subjects: ?? RM ??
Depositing User: Symplectic Admin
Date Deposited: 07 Jan 2016 15:18
Last Modified: 15 Dec 2022 12:18
DOI: 10.1093/jac/dkv039
Publisher's Statement : # The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/ 4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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URI: https://livrepository.liverpool.ac.uk/id/eprint/2044919