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 non-compartmental 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.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. thomas@tropmedres.ac.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. thomas@tropmedres.ac.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pouplin
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam.|Pham Ngoc Thach Hospital, Ho Chi Minh City, Viet Nam.
authors.forename: Nguyen Duc
authors.initials: ND
authors.lastname: Bang
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam.
authors.forename: Pham Van
authors.initials: PV
authors.lastname: Toi
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam.
authors.forename: Pham Nguyen
authors.initials: PN
authors.lastname: Phuong
authors.affiliation: Pham Ngoc Thach Hospital, Ho Chi Minh City, Viet Nam.
authors.forename: Nguyen Huy
authors.initials: NH
authors.lastname: Dung
authors.affiliation: Pham Ngoc Thach Hospital, Ho Chi Minh City, Viet Nam.
authors.forename: Tran Ngoc
authors.initials: TN
authors.lastname: Duong
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam.|Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: Maxine
authors.initials: M
authors.lastname: Caws
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Day
mesh_terms: D000293:Adolescent; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007223:Infant; D007538:Isoniazid / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D008297:Male; D011446:Prospective Studies; D011718:Pyrazinamide / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D012293:Rifampin / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D014390:Tuberculosis, Meningeal / Q000175:diagnosis* / Q000188:drug therapy; D014744:Vietnam
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D001191:Arylamine N-Acetyltransferase; D007538:Isoniazid; D012293:Rifampin
keywords: Anti-tuberculosis drugs; Children; HPLC; Meningitis; Pharmacokinetics; Rifampicin; TB