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

Abstract

BackgroundSuboptimal 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.MethodsWe 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 AUC0–24and Cmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means (95% CIs) of steady-state AUC0–24were 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 AUC0–24for all antituberculosis drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide. N-acetyltransferase2rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants of Cmaxwere generally similar to those for AUC0–24.ConclusionThis 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.

Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia

“…Dose in mg/kg is known to be an important determinant of isoniazid exposure. 32 In a previous modelling study among MDR-TB patients in South Africa, isoniazid at higher doses was found to exhibit non-linear PK. 16 In the current study, however, doses were not found to be significantly associated with isoniazid exposures.…”

“…This might be explained by the small range of mg/kg doses used in the study (IQR 10.4–11.9 mg/kg), which may have obscured the true relationship. Aside from dose in mg/kg, acetylator status based on N -acetyltransferase 2 genotypes or other phenotyping methods has been described as a strong determinant of isoniazid exposure, either in DS-TB patients 32 , 33 or in MDR-TB patients. 11 , 16 , 17 As confirmed by our study, acetylator status is indeed an important determinant of isoniazid exposure, with non-slow acetylators showing a 63% decrease in AUC 0–24 compared with slow acetylators.…”

Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial

“…Considering that young children generally require a longer time for virological suppression after ART initiation, we advise caution when studying OD dosing of dolutegravir in infants on rifampicin-based TB treatment. On top of that, currently recommended dosages of rifampicin have been reported to result in low exposure (AUC) in infants, and higher dosages may therefore be introduced in the near future [ 35 ]. Additionally, studies are exploring the potential use of high-dose rifampicin (up to 35 mg/kg) for children [ 36 , 37 ].…”

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

“…This information can serve as a practical leaflet for clinicians [ 12 , 100 ]. Toxicity and PK related to the clinical outcomes of anti-TB drugs are two crucial aspects of TB research, which have been intensively discussed elsewhere [ 10 , 27 , 31 , 54 , 74 , [100] , [101] , [102] , [103] , [104] , [105] , [106] ]. In the study on AEs surveillance, Ngoc et al [ 104 ] discussed that the administration of long regimens of injectable anti-TB drugs could result in the increased risk of AEs.…”