Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis

Global Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in Pharmacokinetics of Anti-TB Drugs, Fajri Gafar*, Roeland E Wasmann, Helen M McIlleron, Rob E Aarnoutse, H Simon Schaaf, Ben J Marais, Dipti Agarwal, Sampson Antwi, Nguyen D Bang, Adrie Bekker, David J Bell, Chishala Chabala, Louise Choo, Geraint R Davies, Jeremy N Day, Rajeshwar Dayal, Paolo Denti, Peter R Donald, Ephrem EngidaworkAnthony J Garcia-Prats, Diana Gibb, Stephen M Graham, Anneke C Hesseling, Scott K Heysell, Misgana I Idris, Sushil K Kabra, Aarti Kinikar, Agibothu K Hemanth Kumar, Awewura Kwara, Rakesh Lodha, Cecile Magis-Escurra, Nilza Martinez, Binu S Mathew, Vidya Mave, Estomih Mduma, Rachel Mlotha-Mitole, Stellah G Mpagama, Aparna Mukherjee, Heda M Nataprawira, Charles A Peloquin, Thomas Pouplin, Geetha Ramachandran, Jaya Ranjalkar, Vandana Roy, Marieke G G Sturkenboom, Stephanie Thee, Daan J Touw, Katja Taxis, Jasper Stevens, Jan-Willem C Alffenaar

*Corresponding author for this work

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BACKGROUND: Suboptimal exposure to antituberculosis drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line antituberculosis drug pharmacokinetics in children and adolescents at a global level.

METHODS: We systematically searched MEDLINE, Embase, and Web of Science (1990-2021) for pharmacokinetic studies of first-line antituberculosis drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve (AUC0-24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current WHO-recommended paediatric doses. Determinants of AUC0-24 and Cmax were assessed with linear mixed-effects models.

RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means (95% CIs) of steady-state AUC0-24 were summarised for isoniazid (18.7 [15.5-22.6] h·mg·L-1), rifampicin (34.4 [29.4-40.3] h·mg·L-1), pyrazinamide (375.0 [339.9-413.7] h·mg·L-1), and ethambutol (8.0 [6.4-10.0] h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all antituberculosis drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0-24.

CONCLUSION: This study provides the most comprehensive estimates of plasma exposures to first-line antituberculosis drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Original languageEnglish
Article number2201596
Number of pages23
JournalEuropean Respiratory Journal
Early online date3-Nov-2022
Publication statusPublished - 2023

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