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

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. We systematically searched MEDLINE, Embase a...

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Published in:The European respiratory journal Vol. 61; no. 3
Main Authors: 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, Bell, David J, Chabala, Chishala, Choo, Louise, Davies, Geraint R, Day, Jeremy N, Dayal, Rajeshwar, Denti, Paolo, Donald, Peter R, Engidawork, Ephrem, Garcia-Prats, Anthony J, Gibb, Diana, Graham, Stephen M, Hesseling, Anneke C, Heysell, Scott K, Idris, Misgana I, Kabra, Sushil K, Kinikar, Aarti, Kumar, Agibothu K Hemanth, Kwara, Awewura, Lodha, Rakesh, Magis-Escurra, Cecile, Martinez, Nilza, Mathew, Binu S, Mave, Vidya, Mduma, Estomih, Mlotha-Mitole, Rachel, Mpagama, Stellah G, Mukherjee, Aparna, Nataprawira, Heda M, Peloquin, Charles A, Pouplin, Thomas, Ramachandran, Geetha, Ranjalkar, Jaya, Roy, Vandana, Ruslami, Rovina, Shah, Ira, Singh, Yatish, Sturkenboom, Marieke G G, Svensson, Elin M, Swaminathan, Soumya, Thatte, Urmila, Thee, Stephanie, Thomas, Tania A, Tikiso, Tjokosela, Touw, Daan J, Turkova, Anna, Velpandian, Thirumurthy, Verhagen, Lilly M, Winckler, Jana L, Yang, Hongmei, Yunivita, Vycke, Taxis, Katja, Stevens, Jasper, Alffenaar, Jan-Willem C
Format: Journal Article
Language:English
Published: England 01.03.2023
Subjects:
Adolescent
Antitubercular Agents - therapeutic use
Child
Child, Preschool
Ethambutol - therapeutic use
Humans
Isoniazid - therapeutic use
Pyrazinamide - therapeutic use
Rifampin - therapeutic use
ISSN:1399-3003, 1399-3003
Online Access:Get more information
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Summary: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. 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 (AUC ) and peak plasma concentration ( ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC and were assessed with linear mixed-effects models. Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L ), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L ), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L ) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L ). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC for isoniazid and pyrazinamide. -acetyltransferase 2 rapid acetylators had lower isoniazid AUC and slow acetylators had higher isoniazid AUC than intermediate acetylators. Determinants of were generally similar to those for AUC . 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.
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ISSN:1399-3003
1399-3003
DOI:10.1183/13993003.01596-2022