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Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: e01701-16. doi: 10.1128/AAC.01701-16. Print 2017 Feb.

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection.

Author information

1
Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
2
Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
3
Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
4
Department of Medicine, The Miriam Hospital, Providence, Rhode Island, USA.
5
Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
6
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
7
College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
8
Department of Medicine, The Miriam Hospital, Providence, Rhode Island, USA awewura.kwara@medicine.ufl.edu.

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 AUC0-8 values 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 AUC0-8 for 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.).

KEYWORDS:

children; first-line anti-TB drugs; human immunodeficiency virus; pharmacokinetics; tuberculosis

PMID:
27855070
PMCID:
PMC5278726
DOI:
10.1128/AAC.01701-16
[Indexed for MEDLINE]
Free PMC Article

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