Impact of kidney maturation on aminoglycoside exposure in term-born pediatric patients: an in silico study.

Abstract

Background: Kidney function determines aminoglycoside clearance in early life, but its maturation is insufficiently reflected in weight- and age-based dosing. Using in silico studies, we evaluate how kidney function maturation and growth influence aminoglycoside exposure and associated toxicity risks across pediatric development.

Methods: We performed an in silico pharmacokinetic study using a two-compartment model parameterized from pediatric data. Age-homogeneous virtual term-born pediatric cohorts (1 day to 12 years; total N = 10,000) were generated from WHO growth standards and reference values for measured glomerular filtration rates (mGFR). Primary analyses simulated guideline gentamicin dosing (4 mg/kg every 24 h in neonates, 7 mg/kg every 24 h in infants/children) and assessed peak (8-12, 15-20 mg/L) and trough (< 1, < 0.5 mg/L) targets on days 1-10. Amikacin and tobramycin were evaluated in secondary analyses.

Results: Weight and mGFR exhibited different maturation trajectories. Despite guideline-based weight-normalized gentamicin dosing, substantial variation in target attainment was observed. Peak target attainment increased from 34.2% to 70.0%. Trough target attainment increased from < 10% to > 90%, peaking around 2 years of age. Marked age-related heterogeneity persisted within infants: trough target attainment increased > 65% in one year. Sensitivity analyses indicated that exposure was more responsive to changes in glomerular filtration than to weight.

Conclusions: Glomerular filtration maturation is a dominant driver of aminoglycoside exposure in early life. Standard weight-based dosing does not ensure target attainment across the pediatric age range. This supports the development of physiology-informed, model-based dosing strategies accounting for glomerular filtration maturation to improve efficacy while reducing toxicity risks.