Speaker
Description
Aminoglycoside antibiotics are widely used in pediatric care due to their strong activity against Gram-negative bacteria. Dosing remains challenging due to large inter-individual variability in exposure and risks of oto- and nephrotoxicity. As aminoglycosides are predominantly eliminated by renal filtration, developmental changes in body size and kidney function affect exposure.
To quantify the impact of maturation on exposure variability, we built a physiology-informed two-compartment pharmacokinetic model integrating fragmented evidence from pediatric clinical studies. Model parameters, including their variability, were estimated from cross-study allometric regression. The model was applied to age-homogeneous virtual cohorts (N = 1000 per age) constructed from WHO growth data and age-stratified kidney function percentiles. Simulated target attainment reproduces patterns observed in clinical pediatric cohorts.
Age stratification in the virtual cohorts shows that trough attainment increases by >65% between 1-month-old and 2-year-old children under the same weight-based dosing, indicating that mixed-age cohorts conflate maturational changes. Variance decomposition shows that trough variability is maturation-dominated, with kidney function explaining up to 73% of variance in infants and children. Peak variability is insensitive to kidney and body maturation (3–10%) and mostly driven by pharmacokinetic parameter variability.
