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

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.