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Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis
Univ Groningen, Groningen Res Inst Pharm, Unit PharmacoTherapy Epidemiol & Econ, Groningen, Netherlands..ORCID iD: 0000-0002-0084-9018
Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa.;Univ Cape Town, Inst Infect Dis & Mol Med, Wellcome Ctr Infect Dis Res Africa CIDRI Africa, Cape Town, South Africa..ORCID iD: 0000-0002-0982-6226
Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
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2023 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 61, no 3, article id 2201596Article, review/survey (Refereed) Published
Abstract [en]

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 (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax 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 Cmax 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.

Place, publisher, year, edition, pages
European Respiratory Society, 2023. Vol. 61, no 3, article id 2201596
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-510813DOI: 10.1183/13993003.01596-2022ISI: 001042678600001PubMedID: 36328357OAI: oai:DiVA.org:uu-510813DiVA, id: diva2:1794081
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Wellcome trustAvailable from: 2023-09-04 Created: 2023-09-04 Last updated: 2024-01-26Bibliographically approved

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Svensson, Elin M.

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Gafar, FajriMcIlleron, Helen M.Marais, Ben J.Denti, PaoloIdris, Misgana I.Ranjalkar, JayaSvensson, Elin M.Thee, StephanieStevens, Jasper
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