Pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents treated for tuberculous meningitis

OBJECTIVE: To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM). DESIGN: Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis. SETTING: Hasan Sadikin Hospital, Bandung, Indonesia. PATIENTS: Individuals aged 0–18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines. INTERVENTIONS: Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment. MAIN OUTCOME MEASURES: Plasma exposures during the daily dosing interval (AUC(0–24)), peak plasma concentrations (C (max)) and CSF concentrations. RESULTS: Among 20 eligible patients, geometric mean AUC(0–24) of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC(0–24) and C (max) of all drugs. All patients had suboptimal rifampicin AUC(0–24) for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2–3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC(0–24) of isoniazid, rifampicin and pyrazinamide along with C (max) of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05). CONCLUSION: Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies

Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis

Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages. Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I 2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data. Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mgh/L (SEM 2.60) and 38.73 mgh/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies. Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field

Pharmacokinetics of first-line drugs in children with tuberculosis using WHO-recommended weight band doses and formulations

Background: Dispersible paediatric fixed dose combination (FDCs) tablets delivering higher doses of first-line antituberculosis drugs in WHO-recommended weight-bands were introduced in 2015. We report the first pharmacokinetic data for these FDCs in Zambian and South African children in the treatment-shortening SHINE trial. // Methods: Children weighing 4.0-7.9 kg, 8.0-11.9 kg, 12.0-15.9 kg and 16.0-24.9 kg had 1, 2, 3 and 4 tablets daily (rifampicin/isoniazid/pyrazinamide 75/50/150 mg, with or without 100 mg ethambutol, or rifampicin/isoniazid 75/50 mg), respectively. Children 25.0-36.9 kg received doses recommended for adults <37kg (300, 150, 800, 550 mg daily for rifampicin, isoniazid, pyrazinamide, ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. // Results: Of 77 children evaluated, median (IQR) age was 3.7 (1.4-6.6) years, 40 (52%) were male and 20 (26%) HIV-positive. AUC24 for rifampicin, isoniazid, pyrazinamide and ethambutol were 32.5 (20.1-45.1), 16.7 (9.2 - 25.9), 317 (263 - 399) and 9.5 (7.5 – 11.5) mg.h/L, respectively, and lower in children compared to adults for rifampicin in 4.0-7.9 kg, 8-11.9kg and ≥25kg weight-bands, isoniazid in 4.0-7.9kg and ≥25kg, and ethambutol in all five weight-bands. Pyrazinamide exposures were similar to adults. // Conclusions: Recommended weight-band based FDC doses result in lower drug exposures in children in lower weight-bands and in those ≥25kg (on adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current WHO-recommended doses requires further evaluation

Shorter treatment for minimal tuberculosis (TB) in children (SHINE): A study protocol for a randomised controlled trial

BACKGROUND: Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. METHODS/DESIGN: SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. DISCUSSION: Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020

Effects of standard training in the use of closed-circuit televisions in visually impaired adults: design of a training protocol and a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Reading problems are frequently reported by visually impaired persons. A closed-circuit television (CCTV) can be helpful to maintain reading ability, however, it is difficult to learn how to use this device. In the Netherlands, an evidence-based rehabilitation program in the use of CCTVs was lacking. Therefore, a standard training protocol needed to be developed and tested in a randomized controlled trial (RCT) to provide an evidence-based training program in the use of this device.</p> <p>Methods/Design</p> <p>To develop a standard training program, information was collected by studying literature, observing training in the use of CCTVs, discussing the content of the training program with professionals and organizing focus and discussion groups. The effectiveness of the program was evaluated in an RCT, to obtain an evidence-based training program. Dutch patients (n = 122) were randomized into a treatment group: normal instructions from the supplier combined with training in the use of CCTVs, or into a control group: instructions from the supplier only. The effect of the training program was evaluated in terms of: change in reading ability (reading speed and reading comprehension), patients' skills to operate the CCTV, perceived (vision-related) quality of life and tasks performed in daily living.</p> <p>Discussion</p> <p>The development of the CCTV training protocol and the design of the RCT in the present study may serve as an example to obtain an evidence-based training program. The training program was adjusted to the needs and learning abilities of individual patients, however, for scientific reasons it might have been preferable to standardize the protocol further, in order to gain more comparable results.</p> <p>Trial registration</p> <p><url>http://www.trialregister.nl</url>, identifier: NTR1031</p

Predictors of reading literacy for first and second language learners

In this study an attempt was made to construct a multi-factor model predicting the development of reading literacy in the upper grades of primary school in the Netherlands for subgroups of 729 first language (L1) learners and 93 second language (L2) learners. Following a longitudinal design, it was explored to what extent the variation in reading literacy development in L1 and L2 from grade 4 to grade 6 can be explained from children’s word decoding, language, mathematics and nonverbal reasoning skills, reading motivation and self confidence as well as their home reading resources. The results showed that L1 and L2 learners differed in reading literacy skills, language, mathematics, and reasoning skills. Structural equation modelling showed that the reading literacy development in both L1 and L2 learners could be explained from decoding, language, mathematics and reasoning skills, as well as their motivation and self-confidence. A striking difference was the fact that home reading resources had an impact on reading literacy in L1 learners but not in L2 learners

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in &gt;50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019

Clinical standards for the dosing and management of TB drugs

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on ‘best practice´ for dosing and management of TB drugs. METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants. RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified. CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care