title: Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations.
abstract: OBJECTIVE
  The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela.
  
  
  METHODS
  Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined.
  
  
  RESULTS
  25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01).
  
  
  CONCLUSIONS
  We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.
authors.affiliation: Laboratorio de Tuberculosis, Instituto de Biomedicina, Caracas, Venezuela  Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud University Medical Centre, Nijmegen, The Netherlands  Departamento de Pediatría Infectología, Hospital de Niños J.M. de los Ríos, Caracas, Venezuela  Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela  Department of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: L M
authors.initials: LM
authors.lastname: Verhagen
authors.forename: D
authors.initials: D
authors.lastname: López
authors.forename: P W M
authors.initials: PW
authors.lastname: Hermans
authors.forename: A
authors.initials: A
authors.lastname: Warris
authors.forename: R
authors.initials: R
authors.lastname: de Groot
authors.forename: J F
authors.initials: JF
authors.lastname: García
authors.forename: J H
authors.initials: JH
authors.lastname: de Waard
authors.forename: R E
authors.initials: RE
authors.lastname: Aarnoutse
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000293:Adolescent; D000367:Age Factors; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004977:Ethambutol / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007223:Infant; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics; D016018:Least-Squares Analysis; D008297:Male; D044342:Malnutrition / Q000378:metabolism; D011110:Polymorphism, Genetic; D017410:Practice Guidelines as Topic; D011718:Pyrazinamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D014376:Tuberculosis / Q000188:drug therapy* / Q000208:ethnology; D014687:Venezuela; D014944:World Health Organization
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D000123:Acetyltransferases; D007538:Isoniazid; D012293:Rifampin
keywords: TB drugs; Venezuela; WHO drug dose recommendations; children; enfants; medicación anti‐TB; médicaments antituberculeux; niños; recomendación de dosis de la OMS; recommandations de l’OMS pour les doses de médicaments; tuberculose; tuberculosis