Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis
Authors: Gafar Fajri , Wasmann Roeland E. , McIlleron Helen M. , Aarnoutse Rob E. , Schaaf H. Simon , Marais Ben J. , Agarwal Dipti , Antwi Sampson , Bang Nguyen D. , Bekker Adrie , Bell David J. , Chabala Chishala , Choo Louise , Davies Geraint R. , Day Jeremy N. , Dayal Rajeshwar , Denti Paolo , Donald Peter R. , Engidawork Ephrem , Garcia-Prats Anthony J. , Gibb Diana , Graham Stephen M. , Hesseling Anneke C. , Heysell Scott K. , Idris Misgana I. , Kabra Sushil K. , Kinikar Aarti , Kumar Agibothu K. Hemanth , Kwara Awewura , Lodha Rakesh , Magis-Escurra Cecile , Martinez Nilza , Mathew Binu S. , Mave Vidya , Mduma Estomih , Mlotha-Mitole Rachel , Mpagama Stellah G. , Mukherjee Aparna , Nataprawira Heda M. , Peloquin Charles A. , Pouplin Thomas , Ramachandran Geetha , Ranjalkar Jaya , Roy Vandana , Ruslami Rovina , Shah Ira , Singh Yatish , Sturkenboom Marieke G.G. , Svensson Elin M. , Swaminathan Soumya , Thatte Urmila , Thee Stephanie , Thomas Tania A. , Tikiso Tjokosela , Touw Daan J. , Turkova Anna , Velpandian Thirumurthy , Verhagen Lilly M. , Winckler Jana L. , Yang Hongmei , Yunivita Vycke , Taxis Katja , Stevens Jasper , Alffenaar Jan-Willem C. 
Published: November 2022

BackgroundSuboptimal 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.MethodsWe 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 (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were 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 AUC0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis 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.