The European respiratory journal · 2026
Efficacy of isoniazid in paediatric tuberculosis: an individual participant data meta-analysis.
СтатьяМетаанализНазвание и аннотация: Перевод в очереди
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Béranger Agathe, Solans Belén P, Miyakawa Ryo, McIlleron Helen, Tarning Joel, Shah Ira, Aruldhas Blessed Winston, Mathew Binu Susan, Kwara Awewura, Peloquin Charles A, Mukherjee Aparna, Lodha Rakesh, Denti Paolo, Capparelli Edmund V, Kiser Jennifer J, Bekker Adrie, Chabala Chishala, Choo Louise, Turkova Anna, Gafar Fajri, Ruslami Rovina, Nataprawira Heda M, Heysell Scott K, Thomas Tania A, Velpandian Thirumurthy, Day Jeremy N, Bang Nguyen Duc, Dooley Kelly, Savic Radojka M
Аннотация
BACKGROUND: Isoniazid is a cornerstone of management therapy for tuberculosis (TB). Our aim was to determine the association between isoniazid exposure and clinical outcomes, to develop a pharmacokinetic model, and to optimise the dosing regimen in children treated for drug-susceptible (DS)-TB.
METHODS: For this individual participant data meta-analysis, PubMed was searched for observational studies, involving children (aged 0-18 years), being treated for DS-TB. The relationship between isoniazid exposure and clinical outcomes was analysed using a mixed effects logistic regression model. Pharmacokinetic parameters were described using non-linear mixed effects modelling. The pharmacokinetic target was the median adult area under the concentration-time curve at steady-state (AUCss) of 23.4 mg·h·L-1.
RESULTS: Six studies provided clinical outcomes, including 405 patients, of which 21% had unfavourable outcomes. 16 studies (1255 patients) were included in the pharmacokinetic model. Unfavourable outcomes were only related to lower body mass index (BMI) for age z-score (BAZ) (OR 0.96, 95% CI 0.93-0.99; p<0.05). Isoniazid exposure was impacted by N-acetyltransferase 2 (NAT2) genotype, weight, age and nutritional status (using BAZ). With currently recommended World Health Organization (WHO) doses, isoniazid exposure was similar to that of adults. Pharmacokinetic target attainment was 71.7% and 29.5% for slow and fast metabolisers, respectively (p<0.05); 50.5% for patients with BAZ >0 and 42.6% for malnourished patients (BAZ < -2) (p<0.05). The model-informed dosing regimen showed that fast metabolisers could benefit from higher isoniazid dosing, especially in malnourished children.
CONCLUSION: Our findings showed that the only predictor of unfavourable clinical outcomes was a lower BAZ. We support the current WHO-recommended dosing regimen for isoniazid. To equalise and attain our pharmacological target for all children, dosing regimens could be adjusted on NAT2 genotype and nutritional status.
METHODS: For this individual participant data meta-analysis, PubMed was searched for observational studies, involving children (aged 0-18 years), being treated for DS-TB. The relationship between isoniazid exposure and clinical outcomes was analysed using a mixed effects logistic regression model. Pharmacokinetic parameters were described using non-linear mixed effects modelling. The pharmacokinetic target was the median adult area under the concentration-time curve at steady-state (AUCss) of 23.4 mg·h·L-1.
RESULTS: Six studies provided clinical outcomes, including 405 patients, of which 21% had unfavourable outcomes. 16 studies (1255 patients) were included in the pharmacokinetic model. Unfavourable outcomes were only related to lower body mass index (BMI) for age z-score (BAZ) (OR 0.96, 95% CI 0.93-0.99; p<0.05). Isoniazid exposure was impacted by N-acetyltransferase 2 (NAT2) genotype, weight, age and nutritional status (using BAZ). With currently recommended World Health Organization (WHO) doses, isoniazid exposure was similar to that of adults. Pharmacokinetic target attainment was 71.7% and 29.5% for slow and fast metabolisers, respectively (p<0.05); 50.5% for patients with BAZ >0 and 42.6% for malnourished patients (BAZ < -2) (p<0.05). The model-informed dosing regimen showed that fast metabolisers could benefit from higher isoniazid dosing, especially in malnourished children.
CONCLUSION: Our findings showed that the only predictor of unfavourable clinical outcomes was a lower BAZ. We support the current WHO-recommended dosing regimen for isoniazid. To equalise and attain our pharmacological target for all children, dosing regimens could be adjusted on NAT2 genotype and nutritional status.