Adequacy of WHO weight-band dosing and fixed-dose combinations for the treatment of TB in children
DESIGN/METHODS: Children on first-line TB treatment per WHO guidelines were enrolled. Blood sampling at pre-dose, 1, 2, 4, 8, and 12 h post-dose after at least 4 weeks of treatment was performed. Drugs concentrations were measured using validated liquid chromatography tandem with mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Plasma drug exposure below the lower limit of the 95% confidence interval of the mean for children was considered low and above the upper limit was high.
RESULTS: Of 71 participants, 34 (47.9%) had HIV coinfection. The median calculated dose for isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) was 10.0 (range 4.3–13.3), 15.0 (range 8.6–20.0), 30.0 (range 21.0–40.0), and 20.4 (range 14.3–26.7) mg/kg, respectively. Overall, most patients had under-exposure for RIF and PZA and over-exposure for INH and EMB. Drug dose and weight-for-age Z-score were associated with area under the curve from time 0–24 h for all drugs.
CONCLUSIONS: Despite adherence to WHO dosing guidelines, low PZA and RIF plasma exposures were frequent in our study population. Higher than currently recommended dosages of RIF and PZA may be needed in children.
Keywords: antituberculosis drugs; dosing; pediatric; pharmacokinetics; tuberculosis
Document Type: Research Article
Affiliations: 1: Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA, Medical Service, North Florida South Georgia Veterans Health System, Gainesville, FL, USA 2: Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA 3: Directorate of Child Health, Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana 4: Directorate of Child Health, Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana, Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana 5: Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA 6: Department of Clinical Microbiology, KATH, Kumasi, Ghana, Department of Medical Diagnostics, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana 7: Deapratment of Pharmacy, KATH, Kumasi, Ghana 8: Infectious Disease Pharmacokinetics Lab, College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA
Publication date: May 1, 2023
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