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



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. p. 2201596.

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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: 18 Jan 2023 19:43
DOI: 10.1183/13993003.01596-2022
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3166197