Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.
Gafar F., Wasmann RE., McIlleron HM., Aarnoutse RE., Schaaf HS., Marais BJ., Agarwal D., Antwi S., Bang ND., Bekker A., Bell DJ., Chabala C., Choo L., Davies GR., Day JN., Dayal R., Denti P., Donald PR., Engidawork E., Garcia-Prats AJ., Gibb D., Graham SM., Hesseling AC., Heysell SK., Idris MI., Kabra SK., Kinikar A., Kumar AKH., Kwara A., Lodha R., Magis-Escurra C., Martinez N., Mathew BS., Mave V., Mduma E., Mlotha-Mitole R., Mpagama SG., Mukherjee A., Nataprawira HM., Peloquin CA., Pouplin T., Ramachandran G., Ranjalkar J., Roy V., Ruslami R., Shah I., Singh Y., Sturkenboom MGG., Svensson EM., Swaminathan S., Thatte U., Thee S., Thomas TA., Tikiso T., Touw DJ., Turkova A., Velpandian T., Verhagen LM., Winckler JL., Yang H., Yunivita V., Taxis K., Stevens J., Alffenaar J-WC., Global Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in Pharmacokinetics of Anti-TB Drugs None.
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.