Hiwot Hiruy1, Zoe Rogers2, Chris Mbowane3, John Adamson2, Lihle Ngotho2, Farina Karim2, Tawanda Gumbo4, William Bishai5, Prakash Jeena3. 1. Center for Tuberculosis Research, Department of Medicine, JHU, Baltimore, MD 21287, USA. 2. Kwazulu-Natal Research Institute for TB and HIV, Durban 4001, South Africa. 3. Department of Pediatrics, Nelson Mandela School of Medicine, UKZN, Durban 4001, South Africa. 4. Office of Global Health, University of Texas Southwestern Medical School, Dallas, TX 75390, USA. 5. 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.
Abstract
OBJECTIVES: 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.
OBJECTIVES: 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.
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