Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.
Eur Respir J
; 61(3)2023 03.
Article
em En
| MEDLINE
| ID: mdl-36328357
ABSTRACT
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 24â 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)â h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3)â h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7)â h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0)â h·mg·L-1). Our multivariate models indicated that younger age (especially <2â 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Isoniazida
/
Antituberculosos
Tipo de estudo:
Systematic_reviews
Limite:
Adolescent
/
Child
/
Child, preschool
/
Humans
Idioma:
En
Revista:
Eur Respir J
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Holanda