Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India

Ranjalkar, Jaya; Mathew, Sumith K; Verghese, Valsan Philip; Bose, Anuradha; Rose, Winsley; Gupta, Dulari; Fleming, DH; Mathew, Binu

doi:10.1016/j.ijantimicag.2017.12.004

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…Even with improvements in the dosing regimen, pharmacokinetic studies have shown that the currently recommended dosage regimens result in inadequate drug levels in children aged 2 months to 12 years . Similar results have also been observed with earlier regimens in studies from India . Suboptimal blood levels could lead to treatment failure and the emergence of drug resistance .…”

Section: Introductionmentioning

confidence: 61%

“…The present study was conducted at the Clinical Pharmacology Unit and the Departments of Paediatrics and Community Health at Christian Medical College, Vellore, Tamil Nadu, India. The overall clinical efficacy and safety results from this study have been published previously . Children and adolescents aged 2–16 years (hereafter referred to as children) who were newly diagnosed with pulmonary or lymph node tuberculosis with a minimum blood haemoglobin of 10 g dl –1 were recruited (demographic characteristics in Table ).…”

Section: Methodsmentioning

confidence: 99%

“…Rifampicin was measured using a validated HPLC‐UV assay within 72 h of collection. The validation of these assays has been described previously . The lower limit of quantification (LLOQ) for isoniazid and rifampicin were 0.01 μg ml –1 and 0.04 μg ml –1 , respectively.…”

Section: Methodsmentioning

confidence: 99%

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

Aruldhas

Hoglund

Ranjalkar

et al. 2019

Brit J Clinical Pharma

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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.

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Section: Introductionmentioning

confidence: 61%

Section: Methodsmentioning

confidence: 99%

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

Aruldhas

Hoglund

Ranjalkar

et al. 2019

Brit J Clinical Pharma

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“…The majority of the data came from a large phase 3 trial in children with minimal disease (n = 1024; 97% favorable outcomes) [ 34 ]. Only 3 other studies reported >90% favorable outcomes, including 20 [ 23 ], 27 [ 29 ], and 37 children [ 33 ]. Studies using daily WHO-recommended doses reported 81% of favorable outcomes.…”

Section: Resultsmentioning

confidence: 99%

Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis

Solans

Béranger

Radtke

et al. 2023

Clinical Infectious Diseases

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Background Optimal doses of first line drugs for drug-susceptible tuberculosis (DS-TB) treatment in children and young adolescents remain uncertain. We aimed to determine if children treated using WHO-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic exposures. Methods Titles, abstracts, and full-text articles were screened. We searched Pubmed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children <18 years, being treated for DS-TB with rifampicin, pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO, CRD42021274222. Results Of 304 studies identified, 46 studies were eligible for full-text review and 12 and 18 articles were included for the efficacy and pharmacokinetic analysis, respectively. Of 1,830 children included in the efficacy analysis, 82% had favourable outcomes (range 25%-95%). At WHO-recommended doses, exposures to rifampicin, pyrazinamide, and ethambutol were lower in children as compared to adults. Children ≤6 years have 35% lower AUC than older children (14.4 (9.9-18.8) vs 22.0 (13.8-30.1) μg.h/mL) and children with HIV (CWHIV) had 35% lower rifampicin AUC than HIV negative children (17.3 (11.4-23.2) vs 26.5 (21.3-31.7) μg.h/mL). Heterogeneity and small sample sizes were major limitations. Conclusion There is large variability in outcomes with an average 82% favourable outcomes. Drug exposures are lower in children than in adults. Younger children and CWHIV are underexposed to rifampicin. Standardization of pharmacokinetic paediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.

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“…This finding was confirmed by a study involving 39 children with active TB aged 2–16 years conducted by Ranjalkar et al in 2017. No significant effect of sex, age, body weight, type of TB, nutritional status and treatment regimen on plasma concentrations of either INH or RIF was observed [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Real-life isoniazid and rifampicin plasma concentrations in children: a tool for therapeutic drug monitoring of tuberculosis

et al. 2021

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Background Low plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages. Methods Children with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method. Results In all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (≤ 2 years, 2–12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range. Conclusions Based on our findings, monitoring patients’ drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.

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Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India

Cited by 10 publications

References 30 publications

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

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

Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis

Real-life isoniazid and rifampicin plasma concentrations in children: a tool for therapeutic drug monitoring of tuberculosis

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