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BACKGROUND: Dried blood spot (DBS) sampling is a blood collection tool that uses a finger prick to obtain a blood drop on a dried blood spot card. It can be used for therapeutic drug monitoring, a method that uses blood drug concentrations to optimize individual treatment. DBS sampling is thought to be a simpler way of blood collection compared to venous sampling. The

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.

The aim of this study was to evaluate the difference in drug exposure of rifampicin in native versus non-native Paraguayan populations using dried blood spots (DBS) samples collected utilizing a limited sampling strategy. This was a prospective pharmacokinetic study that enrolled hospitalized tuberculosis (TB) patients from both native and non-native populations receiving oral rifampicin 10 mg/kg once-daily dosing. Steady-state DBS samples were collected at 2, 4, and 6 h after intake of rifampicin. The area under the time concentration curve 0–24 h (AUC0–24) was calculated using a Bayesian population PK model. Rifampicin AUC0–24 < 38.7 mg*h/L was considered as low. The probability of target attainment (PTA) was calculated using AUC0–24/MIC > 271 as a target and estimated MIC values of 0.125 and 0.25 mg/L. In total, 50 patients were included. Native patients (n = 30) showed comparable drug exposure to the non-natives (n = 20), median AUC0–24 24.7 (17.1–29.5 IQR) and 21.6 (15.0–35.4 IQR) mg*h/L (p = 0.66), respectively. Among total patients, only 16% (n = 8) had a rifampicin AUC0–24 > 38.7 mg*h/L. Furthermore, PTA analysis showed that only 12 (24%) of the patients met a target AUC0–24 /MIC ≥ 271, assuming an MIC of 0.125 mg/L, which plummeted to 0% at a wild-type MIC of 0.25 mg/L. We successfully used DBS and limited sampling for the AUC0–24 estimation of rifampicin. Currently, our group, the EUSAT-RCS consortium, is preparing a prospective multinational, multicenter phase IIb clinical trial evaluating the safety and efficacy of high-dose rifampicin (35 mg/kg) in adult subjects using the DBS technique for AUC0–24 estimation.

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