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

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 (AUC(0-24)) and peak plasma concentration (C-max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC(0-24) 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 AUC(0-24) for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC(0-24) for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC(0-24) and slow acetylators had higher isoniazid AUC(0-24) than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC(0-24). 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.

Automated summary

This study aims to investigate the pharmacokinetics of first-line anti-TB drugs in children and adolescents globally. The results show that younger age and HIV-positive status are associated with lower AUC(0-24) for all first-line anti-TB drugs, while severe malnutrition is associated with lower AUC(0-24) for isoniazid and pyrazinamide. The determinants of Cmax are generally similar to those of AUC(0-24).