Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

Aims Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. Methods Data were collected from 41 children, aged 2–16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed‐effects model. Results Isoniazid pharmacokinetics were described by a one‐compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one‐compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed‐dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed‐dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg–1, was found to provide adequate drug exposure in most children. Conclusions The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose–effect relationship of higher doses of rifampicin

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

Aims Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. Methods Data were collected from 41 children, aged 2–16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed‐effects model. Results Isoniazid pharmacokinetics were described by a one‐compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one‐compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed‐dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed‐dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg–1, was found to provide adequate drug exposure in most children. Conclusions The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose–effect relationship of higher doses of rifampicin

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

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

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

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 (AUC(0-24)) and peak plasma concentration (C (max)) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC(0-24) and C (max) 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 AUC(0-24) 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 AUC(0-24) for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC(0-24) for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC(0-24) and slow acetylators had higher isoniazid AUC(0-24) than intermediate acetylators. Determinants of C (max) were generally similar to those for AUC(0-24). 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

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

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 AUC0-24 and Cmax were 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 AUC0-24 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 0-24 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.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