title: Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection.
abstract: Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC0-8), maximum concentration (Cmax), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P < 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC0-8values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC0-8for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).
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
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
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: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Anima M
authors.initials: AM
authors.lastname: Sarfo
authors.affiliation: Department of Medicine, The Miriam Hospital, Providence, Rhode Island, USA.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Fizza S
authors.initials: FS
authors.lastname: Gillani
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.
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: Orstin
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Theresa
authors.initials: T
authors.lastname: Opoku
authors.affiliation: Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bosomtwe
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, 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, Cape Town, South Africa.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Norman
authors.affiliation: College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.affiliation: Department of Medicine, The Miriam Hospital, Providence, Rhode Island, USA awewura.kwara@medicine.ufl.edu.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Awewura
authors.initials: A
authors.lastname: Kwara
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000995:Antitubercular Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D060085:Coinfection / Q000188:drug therapy; D004977:Ethambutol / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D007538:Isoniazid / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D011718:Pyrazinamide / Q000097:blood / Q000493:pharmacokinetics; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics; D014376:Tuberculosis / Q000188:drug therapy* / Q000821:virology
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin
keywords: children; first-line anti-TB drugs; human immunodeficiency virus; pharmacokinetics; tuberculosis