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

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. 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 ) and peak plasma concentration ( ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC and were assessed with linear mixed-effects models. Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L ), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L ), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L ) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L ). Our multivariate models indicated that younger age (especially