Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis

Abstract

Background: Among the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30 % mortality and 50 % of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen. Methods: We performed a prospective observational study of 100 consecutively treated children (≤15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled noncompartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or > 4 years of age. Results: Younger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with −14 %, −22 % and −16 % for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children. Conclusions: There is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.

Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

“…Isoniazid is an important part of the first line treatment for TBM due to high early bactericidal activity within the first 2 days of treatment and its excellent CSF penetration . The CSF‐to‐plasma free concentration ratio (AUC total,CSF /AUC unbounded,plasma ) was estimated to be close to 1 (1.11) in the current study using a reported plasma protein binding of 14% .…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…The lung cavity and surrounding fibrosis, depending on the size, will create a physicochemical barrier to drug entry, leading to anatomical site-based monotherapy. Indeed, this differ ential penetration has also been identified in pericardial 194 and meningeal 195 tuberculosis.…”

Suboptimal Exposure to Anti‐TB Drugs in a TBM/HIV+ Population Is Not Related to Antiretroviral Therapy

“…A recent study has investigated, in children with TBM, the CSF exposure to anti-tubercular drugs and found that at a dose of 10mg/kg, rifampicin levels are lower than the minimum inhibitory concentration of susceptible bacteria 32 . The reasons behind the low RIF exposure in this cohort are unknown, and whether HIV status is the driving force behind the low exposure has been a subject of debate as previously discussed in the introduction.…”