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

Abstract

ObjectiveTo assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).DesignProspective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.SettingHasan Sadikin Hospital, Bandung, Indonesia.PatientsIndividuals aged 0–18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines.InterventionsPlasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment.Main outcome measuresPlasma exposures during the daily dosing interval (AUC0–24), peak plasma concentrations (Cmax) and CSF concentrations.ResultsAmong 20 eligible patients, geometric mean AUC0–24 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 AUC0–24 and Cmax of all drugs. All patients had suboptimal rifampicin AUC0–24 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. AUC0–24 of isoniazid, rifampicin and pyrazinamide along with Cmax of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05).ConclusionHigher 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.

Treatment Outcomes of Childhood Tuberculous Meningitis in a Real-World Retrospective Cohort, Bandung, Indonesia

“…This short-course, high-dose therapy has recently been added by WHO as an alternative treatment option for childhood TBM ( 41 ). Suboptimal plasma and CSF concentrations with standard doses of oral rifampin at 10–20 mg/kg/day in children with TBM have also been reported in recent pharmacokinetic studies ( 42 , 43 ), advocating the use of higher rifampin doses with further efficacy and safety evaluations.…”

Pharmacokinetics of Antituberculosis Drugs in Plasma and Cerebrospinal Fluid in a Patient with Pre-Extensive Drug Resistant Tuberculosis Meningitis

“… 34 , 35 In order to formulate an effective therapeutic regimen, we adopted high-dose isoniazid (800mg/d) and found that its CSF concentration reached a maximum (11.57 ug/mL) 6 hours after administration, which mean about 100% brain penetration and promised an effective bactericidal activity in the brain. 29 After WGS of our patient’s CSF showed susceptibility of isoniazid, we lowered the isoniazid dose to 600 mg/d. Peripheral neuropathy is the most common toxicity from long-term use of isoniazid.…”

Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability

“…Several first-line anti-tuberculosis drugs (e.g., rifampicin and ethambutol) have poor penetration across the blood-brain and the blood-CSF barriers [63]. Rifampicin remains an essential medication for TBM [64] but standard dosing yields CSF concentrations that are below the minimal inhibitory concentration (MIC) for M. tuberculosis in a large proportion of patients, including children [65][66][67]. A recent model-based meta-analysis using emerging data from adult trials showed a strong positive correlation between rifampicin concentrations and survival, with doses of at least 30 mg/kg predicted to improve survival substantially compared to 10 mg/kg [68].…”