title: Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations.
abstract: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dosage recommendations for children. No pharmacokinetic studies for these revised dosages are available for children <2 years. The aim of the study was to document the pharmacokinetics of the first-line anti-TB agents in children <2 years of age comparing previous and revised WHO dosages of isoniazid (INH; 5 versus 10 mg/kg/day), rifampin (RMP; 10 versus 15 mg/kg/day), and pyrazinamide (PZA; 25 versus 35 mg/kg/day) and to investigate the effects of clinical covariates, including HIV coinfection, nutritional status, age, gender, and type of tuberculosis (TB), and the effect of NAT2 acetylator status. Serum INH, PZA, and RMP levels were prospectively assessed in 20 children <2 years of age treated for TB following the previous and the revised WHO dosage recommendations. Samples were taken prior to dosing and at 0.5, 1.5, 3, and 5 h following dosing. The maximum drug concentration in serum (C(max)), the time to C(max) (t(max)), and the area under the concentration-time curve (AUC) were calculated. Eleven children had pulmonary and 9 had extrapulmonary TB. Five were HIV infected. The mean C(max) (μg/ml) following the administration of previous/revised dosages were as follows: INH, 3.19/8.11; RMP, 6.36/11.69; PZA, 29.94/47.11. The mean AUC (μg·h/ml) were as follows: INH, 8.09/20.36; RMP, 17.78/36.95; PZA, 118.0/175.2. The mean C(max) and AUC differed significantly between doses. There was no difference in the t(max) values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.
authors.affiliation: Department of Paediatric Pneumology and Immunology, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Thee
authors.forename: J A
authors.initials: JA
authors.lastname: Seddon
authors.forename: P R
authors.initials: PR
authors.lastname: Donald
authors.forename: H I
authors.initials: HI
authors.lastname: Seifart
authors.forename: C J
authors.initials: CJ
authors.lastname: Werely
authors.forename: A C
authors.initials: AC
authors.lastname: Hesseling
authors.forename: B
authors.initials: B
authors.lastname: Rosenkranz
authors.forename: S
authors.initials: S
authors.lastname: Roll
authors.forename: K
authors.initials: K
authors.lastname: Magdorf
authors.forename: H S
authors.initials: HS
authors.lastname: Schaaf
mesh_terms: D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002675:Child, Preschool; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D009752:Nutritional Status; D017410:Practice Guidelines as Topic / Q000592:standards*; D011718:Pyrazinamide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology; D014944:World Health Organization
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin