Population pharmacokinetics of pyrazinamide and ethambutol in children with tuberculosis with or without HIV

Abstract

Tuberculosis (TB) is a major cause of morbidity and mortality in children globally. This study developed models to describe population pharmacokinetics (PK) of pyrazinamide (PZA) and ethambutol (EMB) in children with TB with or without human immunodeficiency virus (HIV) coinfection. Ghanaian children with TB with or without HIV coinfection receiving first-line antituberculosis therapy for at least 4 weeks had blood samples collected at time 0 (pre-dose), 1-, 2-, 4-, 8-, and 12-h post-dose. PZA and EMB concentrations were quantified using liquid chromatography tandem mass spectrometry. Nonlinear mixed-effects models were applied to describe the population PK using Monolix2024R1. Maximum concentrations (<i>C</i>_max) and 24-h area under the time concentration curve (AUC_0-24) were compared to published values in adults. A total of 85 children (41 TB, 44 TB/HIV) were included. The median (range) age was 5 years (0.3-14.5), and 61.2% were male. Median (range) doses for PZA and EMB were 31.6 (21.4-49.7) and 21.4 mg/kg (14.3-34.2), respectively. PZA was best described using a one-compartment model and EMB by a two-compartment model. Allometric scaling improved both model fits. Children with TB/HIV coinfection had approximately 18.5% faster PZA clearance and 25% faster EMB clearance. Optimized dosing to achieve adult-equivalent exposures required higher-than-currently recommended doses, particularly among children in the lowest weight bands and those with HIV. The population PK of PZA and EMB was well described by the final models, but the higher-than-currently recommended doses needed to achieve adult-equivalent exposures raise concerns regarding risks for drug-associated toxicities and will require further evaluation.