UCSF

BACKGROUND: Tuberculosis affects over one million children annually. Ethambutol (EMB) is a key component of first-line therapy, but comprehensive pediatric pharmacokinetic studies have been lacking. METHODS: EMB concentrations and individual-level patient data from 3 studies were analyzed using nonlinear mixed effects modeling. Simulations compared current World Health Organization (WHO)-recommended doses and model-informed optimized doses. Target exposure distribution (area under the curve, 13.8-17.7 mg·h/L), which had been previously established in adult clinical trials, guided dose optimization. RESULTS: A total of 220 participants (0.2-15 years; 3.6 and 43.0 kg) contributed 1085 plasma EMB concentrations for model development. Weight effects were incorporated for clearance (CL), intercompartmental CL, and volumes of distribution in central and peripheral compartments. Age affected CL through a maturation function. Simulations indicated children weighing <25 kg had median exposures below target exposure distribution at current WHO-recommended doses. Optimized weight-band dosing would increase doses in approximately 40.5% of the patients, with an additional 5% potentially benefiting. CONCLUSIONS: Our individual patient data meta-analysis supports the revision of current pediatric EMB dosing guidelines for the treatment of tuberculosis. Our findings aim to ensure adequate drug exposure across all pediatric weight bands, while also accounting for toxicity and challenges related to formulation implementation and adherence.