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

Fajri Gafar ORCID logo ; Roeland E Wasmann ; Helen M McIlleron ; Rob E Aarnoutse ; H Simon Schaaf ORCID logo ; Ben J Marais ORCID logo ; Dipti Agarwal ; Sampson Antwi ; Nguyen D Bang ; Adrie Bekker ; +55 more... David J Bell ; Chishala Chabala ORCID logo ; Louise Choo ; Geraint R Davies ; Jeremy N Day ; Rajeshwar Dayal ; Paolo Denti ; Peter R Donald ; Ephrem Engidawork ORCID logo ; Anthony J Garcia-Prats ORCID logo ; Diana Gibb ORCID logo ; Stephen M Graham ORCID logo ; 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 ORCID logo ; Rachel Mlotha-Mitole ; Stellah G Mpagama ; Aparna Mukherjee ; Heda M Nataprawira ; Charles A Peloquin ; Thomas Pouplin ; Geetha Ramachandran ; Jaya Ranjalkar ; Vandana Roy ; Rovina Ruslami ; Ira Shah ; Yatish Singh ; Marieke GG Sturkenboom ; Elin M Svensson ; Soumya Swaminathan ; Urmila Thatte ; Stephanie Thee ORCID logo ; Tania A Thomas ; Tjokosela Tikiso ; Daan J Touw ; Anna Turkova ORCID logo ; Thirumurthy Velpandian ; Lilly M Verhagen ; Jana L Winckler ; Hongmei Yang ; Vycke Yunivita ; Katja Taxis ; Jasper Stevens ; Jan-Willem C Alffenaar ORCID logo ; Global Collaborative Group for Meta-Analysis of Paediatric Indiv ; (2023) Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis. The European respiratory journal, 61 (3). p. 2201596. ISSN 0903-1936 DOI: 10.1183/13993003.01596-2022
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BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB 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 anti-TB 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 from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max 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 of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 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 first-line anti-TB 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 C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB 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.


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