TY - JOUR
T1 - Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents
T2 - a systematic review and individual patient data meta-analysis
AU - Global Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in Pharmacokinetics of Anti-TB Drugs
AU - Gafar, Fajri
AU - Wasmann, Roeland E
AU - McIlleron, Helen M
AU - Aarnoutse, Rob E
AU - Schaaf, H Simon
AU - Marais, Ben J
AU - Agarwal, Dipti
AU - Antwi, Sampson
AU - Bang, Nguyen D
AU - Bekker, Adrie
AU - Bell, David J
AU - Chabala, Chishala
AU - Choo, Louise
AU - Davies, Geraint R
AU - Day, Jeremy N
AU - Dayal, Rajeshwar
AU - Denti, Paolo
AU - Donald, Peter R
AU - Engidawork, Ephrem
AU - Garcia-Prats, Anthony J
AU - Gibb, Diana
AU - Graham, Stephen M
AU - Hesseling, Anneke C
AU - Heysell, Scott K
AU - Idris, Misgana I
AU - Kabra, Sushil K
AU - Kinikar, Aarti
AU - Hemanth Kumar, Agibothu K
AU - Kwara, Awewura
AU - Lodha, Rakesh
AU - Magis-Escurra, Cecile
AU - Martinez, Nilza
AU - Mathew, Binu S
AU - Mave, Vidya
AU - Mduma, Estomih
AU - Mlotha-Mitole, Rachel
AU - Mpagama, Stellah G
AU - Mukherjee, Aparna
AU - Nataprawira, Heda M
AU - Peloquin, Charles A
AU - Pouplin, Thomas
AU - Ramachandran, Geetha
AU - Ranjalkar, Jaya
AU - Roy, Vandana
AU - Sturkenboom, Marieke G G
AU - Thee, Stephanie
AU - Touw, Daan J
AU - Taxis, Katja
AU - Stevens, Jasper
AU - Alffenaar, Jan-Willem C
N1 - Copyright ©The authors 2022. For reproduction rights and permissions contact [email protected].
PY - 2023
Y1 - 2023
N2 - BACKGROUND: 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.METHODS: 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 (AUC0-24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current WHO-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 (95% CIs) of steady-state AUC0-24 were summarised for isoniazid (18.7 [15.5-22.6] h·mg·L-1), rifampicin (34.4 [29.4-40.3] h·mg·L-1), pyrazinamide (375.0 [339.9-413.7] h·mg·L-1), and ethambutol (8.0 [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 antituberculosis 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.CONCLUSION: 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.
AB - BACKGROUND: 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.METHODS: 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 (AUC0-24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current WHO-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 (95% CIs) of steady-state AUC0-24 were summarised for isoniazid (18.7 [15.5-22.6] h·mg·L-1), rifampicin (34.4 [29.4-40.3] h·mg·L-1), pyrazinamide (375.0 [339.9-413.7] h·mg·L-1), and ethambutol (8.0 [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 antituberculosis 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.CONCLUSION: 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.
U2 - 10.1183/13993003.01596-2022
DO - 10.1183/13993003.01596-2022
M3 - Review article
C2 - 36328357
SN - 0903-1936
VL - 61
JO - European Respiratory Journal
JF - European Respiratory Journal
M1 - 2201596
ER -