Gafar, Fajri, Wasmann, Roeland E, McIlleron, Helen M, Aarnoutse, Rob E, Schaaf, H Simon, Marais, Ben J, Agarwal, Dipti, Antwi, Sampson, Bang, Nguyen D, Bekker, Adrie et al (show 55 more authors)
(2022)
Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.
The European respiratory journal, 61 (3).
p. 2201596.
|
Text
Gafar ERJ author accepted version (1).pdf - Author Accepted Manuscript Download (11MB) | Preview |
Abstract
<h4>Background</h4>Suboptimal exposure to antituberculosis drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line antituberculosis drug pharmacokinetics in children and adolescents at a global level.<h4>Methods</h4>We systematically searched MEDLINE, Embase, and Web of Science (1990-2021) for pharmacokinetic studies of first-line antituberculosis 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 (AUC<sub>0-24</sub>) and peak plasma concentration (C<sub>max</sub>) were assessed with random-effects models, normalised with current WHO-recommended paediatric doses. Determinants of AUC<sub>0-24</sub> and C<sub>max</sub> were assessed with linear mixed-effects models.<h4>Results</h4>Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means (95% CIs) of steady-state AUC<sub>0-24</sub> were summarised for isoniazid (18.7 [15.5-22.6] h·mg·L<sup>-1</sup>), rifampicin (34.4 [29.4-40.3] h·mg·L<sup>-1</sup>), pyrazinamide (375.0 [339.9-413.7] h·mg·L<sup>-1</sup>), and ethambutol (8.0 [6.4-10.0] h·mg·L<sup>-1</sup>). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC<sub>0-24</sub> for all antituberculosis drugs, while severe malnutrition was associated with lower AUC<sub>0-24</sub> for isoniazid and pyrazinamide. N-acetyltransferase <i>2</i> rapid acetylators had lower isoniazid AUC<sub>0-24</sub> and slow acetylators had higher isoniazid AUC<sub>0-24</sub> than intermediate acetylators. Determinants of C<sub>max</sub> were generally similar to those for AUC<sub>0-24</sub>.<h4>Conclusion</h4>This study provides the most comprehensive estimates of plasma exposures to first-line antituberculosis 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.
| Item Type: | Article |
|---|---|
| Additional Information: | Source info: THELANCETID-D-22-01375 |
| Uncontrolled Keywords: | Global Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in Pharmacokinetics of Anti-TB Drugs |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 Nov 2022 09:12 |
| Last Modified: | 03 Nov 2023 02:30 |
| DOI: | 10.1183/13993003.01596-2022 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3166197 |
Dimensions
Dimensions
