Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: The PHATISA study

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 whowere 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 factorwas 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 weightbased dosages.