title: Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection.
abstract: BACKGROUND
  Pharmacokinetic data on the first-line antituberculosis drugs using the World Health Organization (WHO) revised dosages for children are limited. We investigated the pharmacokinetics of these drugs in children who were mostly treated with revised dosages.
  
  
  METHODS
  Children with tuberculosis on first-line therapy for at least 4 weeks had blood samples collected at predose, 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography mass spectrometry methods, and pharmacokinetic parameters were calculated using noncompartmental analysis. Factors associated with plasma peak concentration (Cmax) and the area under the time-concentration curve 0-8 hours (AUC0-8h) of each drug was examined using univariate and multivariate analysis.
  
  
  RESULTS
  Of the 62 children, 32 (51.6%) were male, 29 (46.8%) were younger than 5 years old, and 28 (45.2%) had human immunodeficiency virus (HIV) coinfection. Three patients had undetectable pyrazinamide and ethambutol concentrations. The median (interquartile range) AUC0-8hfor isoniazid was 17.7 (10.2-23.4) µg·h mL-1, rifampin was 26.0 (15.3-36.1) µg·h mL-1, pyrazinamide was 144.6 (111.5-201.2) µg·h mL-1, and ethambutol was 6.7 (3.8-10.4) µg·h mL-1. Of the children who received recommended weight-band dosages, 44/51 (86.3%), 46/56 (82.1%), 27/56 (48.2%), and 21/51 (41.2%) achieved target Cmaxfor isoniazid, pyrazinamide, ethambutol, and rifampin, respectively. In multivariate analysis, age, sex, HIV coinfection status, and drug dosage in milligrams per kilogram were associated with the drugs' plasma drug Cmaxor AUC0-8h.
  
  
  CONCLUSIONS
  The revised dosages appeared to be adequate for isoniazid and pyrazinamide, but not for rifampin or ethambutol in this population. Higher dosages of rifampin and ethambutol than currently recommended may be required in most children.
authors.affiliation: Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.|Department of Medicine, The Miriam Hospital, Providence, Rhode Island.
authors.forename: Awewura
authors.initials: A
authors.lastname: Kwara
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.|Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: Anthony
authors.initials: A
authors.lastname: Enimil
authors.affiliation: Department of Medicine, The Miriam Hospital, Providence, Rhode Island.
authors.forename: Fizza S
authors.initials: FS
authors.lastname: Gillani
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, New York.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Anima M
authors.initials: AM
authors.lastname: Sarfo
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Albert
authors.initials: A
authors.lastname: Dompreh
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Ortsin
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Osei-Tutu
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kwarteng Owusu
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Norman
authors.affiliation: Department of Medicine, The Miriam Hospital, Providence, Rhode Island.
authors.forename: Jaclynn
authors.initials: J
authors.lastname: Kurpewski
authors.affiliation: College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.|Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ansong
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.|Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: Sampson
authors.initials: S
authors.lastname: Antwi
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D060085:Coinfection / Q000188:drug therapy; D005260:Female; D005869:Ghana; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D007223:Infant; D008297:Male; D013058:Mass Spectrometry; D017410:Practice Guidelines as Topic; D011446:Prospective Studies; D014376:Tuberculosis / Q000150:complications* / Q000188:drug therapy*; D014944:World Health Organization
chemical_list: D000995:Antitubercular Agents
keywords: children; first-line antituberculosis drugs; pharmacokinetics; revised WHO dosage; tuberculosis