Publication: Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis
Issued Date
2016
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eng
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Mahidol University
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BioMed Central
Bibliographic Citation
BMC Infectious Diseases. Vol.16, (2016), 144
Suggested Citation
Pouplin, Thomas, Nguyen Duc Bang, Pham Van Toi, Pham Nguyen Phuong, Nguyen Huy Dung, Tran Ngoc Duong, Caws, Maxine, Thwaites, Guy E., Tarning, Joel, Day, Jeremy N. Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis. BMC Infectious Diseases. Vol.16, (2016), 144. doi:10.1186/s12879-016-1470-x Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/3156
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Title
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.