title: Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study.
abstract: OBJECTIVE
  There is a paucity of evidence regarding the optimal dosing of anti-TB drugs in children. The aim of this study was to identify the pharmacokinetic parameters of first-line anti-TB drugs and the concentrations achieved after implementation of the 2010 WHO-recommended paediatric dosages.
  
  
  METHODS
  We conducted a prospective, observational pharmacokinetic study in children 10 years old or younger who were on isoniazid, rifampicin, pyrazinamide and ethambutol therapy in Durban, KwaZulu-Natal, South Africa. Blood was collected at six timepoints over a 24 h period, chosen using optimal sampling theory. The drug concentrations were simultaneously modelled to identify the compartmental pharmacokinetics of each drug in each child, using the ADAPT program.
  
  
  RESULTS
  The best six sampling timepoints in children were identified as 0 (pre-dose) and 0.42, 1.76, 3.37, 10.31 and 24 h post-dose. Thirty-one children were recruited and blood was drawn at these timepoints. Rifampicin, ethambutol and pyrazinamide were best described using a one-compartment model, while isoniazid was best described with a two-compartment model. Only 2/31 (6%), 20/31 (65%), 17/31 (55%) and 2/13 (15%) of children attained the WHO 2 h target therapeutic concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. Moreover, only 24/31 (77%), 6/31 (19%) and 8/31 (26%) achieved the AUCs associated with an optimal clinical response to rifampicin, pyrazinamide and isoniazid, respectively. No single risk factor was significantly associated with below-normal drug levels.
  
  
  CONCLUSIONS
  The drug concentrations of all first-line anti-TB drugs were markedly below the target therapeutic concentrations in most South African children who received the revised WHO-recommended paediatric weight-based dosages.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, JHU, Baltimore, MD 21287, USA.
authors.forename: Hiwot
authors.initials: H
authors.lastname: Hiruy
authors.affiliation: Kwazulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Rogers
authors.affiliation: Department of Pediatrics, Nelson Mandela School of Medicine, UKZN, Durban 4001, South Africa.
authors.forename: Chris
authors.initials: C
authors.lastname: Mbowane
authors.affiliation: Kwazulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Adamson
authors.affiliation: Kwazulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: Lihle
authors.initials: L
authors.lastname: Ngotho
authors.affiliation: Kwazulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa.
authors.forename: Farina
authors.initials: F
authors.lastname: Karim
authors.affiliation: Office of Global Health, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, JHU, Baltimore, MD 21287, USA Kwazulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA wbishai@jhmi.edu.
authors.forename: William
authors.initials: W
authors.lastname: Bishai
authors.affiliation: Department of Pediatrics, Nelson Mandela School of Medicine, UKZN, Durban 4001, South Africa.
authors.forename: Prakash
authors.initials: P
authors.lastname: Jeena
mesh_terms: D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D013019:South Africa; D013997:Time Factors; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents
keywords: anti-tuberculosis drug pharmacokinetics; paediatric pharmacokinetics; paediatric tuberculosis