title: Age, nutritional status and INH acetylator status affect pharmacokinetics of anti-tuberculosis drugs in children.
abstract: METHODS
  The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children.
  
  
  OBJECTIVE
  To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes.
  
  
  METHODS
  Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes.
  
  
  CONCLUSIONS
  Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.
authors.affiliation: National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India.
authors.forename: G
authors.initials: G
authors.lastname: Ramachandran
authors.forename: A K
authors.initials: AK
authors.lastname: Hemanth Kumar
authors.forename: P K
authors.initials: PK
authors.lastname: Bhavani
authors.forename: N
authors.initials: N
authors.lastname: Poorana Gangadevi
authors.forename: L
authors.initials: L
authors.lastname: Sekar
authors.forename: D
authors.initials: D
authors.lastname: Vijayasekaran
authors.forename: V V
authors.initials: VV
authors.lastname: Banu Rekha
authors.forename: S
authors.initials: S
authors.lastname: Ramesh Kumar
authors.forename: N
authors.initials: N
authors.lastname: Ravichandran
authors.forename: G
authors.initials: G
authors.lastname: Mathevan
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000107:Acetylation; D000367:Age Factors; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007194:India; D007223:Infant; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D015999:Multivariate Analysis; D009752:Nutritional Status; D010641:Phenotype; D011718:Pyrazinamide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012044:Regression Analysis; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin