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 AUC(0–24) 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 C(max) 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.