Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations.

Abstract

Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) 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. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration (Cmax) and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for N-acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).