Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis
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;
+55 more...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 GG;
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;
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: https://doi.org/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.
