Pharmacokinetics and Dose Optimization of Ethambutol in Children on First-line Antituberculosis Therapy: An...

Tuberculosis affects over a million children annually. Ethambutol (EMB) is a key component of the standard four-drug therapy for drug-susceptible tuberculosis in children, yet comprehensive pharmacokinetic studies have been lacking. We characterized the population pharmacokinetics of EMB through an individual patient data meta-analysis to determine optimal dosing strategies.

EMB concentrations and individual-level patient data from three 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 (AUC 13.8-17.7 mg·h/L), which had been previously established in adult clinical trials, guided dose optimization.

A total of 220 participants, aged from 0.2 to 15 years and weighing between 3.6 and 43.0 kg, contributed 1,085 plasma concentrations of EMB for model development. The effect of weight was incorporated on clearance, intercompartmental clearance, and volume of distribution in both the central and peripheral compartments. Age affected clearance through a maturation function. Simulations indicated children weighing less than 25 kg had median exposures below the target exposure distribution at current WHO-recommended doses. Under the optimized weight band dosing, approximately 40.5% of the patients would receive a higher dose, and an additional 5% points of patients may benefit from this adjustment.

Our IPDMA 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.