Personalized tobramycin dosing in children with cystic fibrosis: an AUC₂₄-guided approach

Tobramycin is commonly used for the treatment of pulmonary exacerbations in children with cystic fibrosis (CF). Currently, a standard dose of 10 mg/kg daily is used in all children. We aim to develop a population pharmacokinetic (popPK) model of tobramycin in children with CF and determine the: (i) effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on tobramycin pharmacokinetics (PK); (ii) attainment of the commonly used serum steady state area under the concentration-time curve target (AUC_24,ss) of 80-110 mg/L⋅h with standard dosing; and (iii) generate an optimized fully individualized dosing strategy to improve target attainment. Multicenter prospective observational study of children with CF aged 0-19 years receiving IV tobramycin who had ≥1 serum concentration measured. A popPK model was developed using nonlinear mixed-effect modeling, and simulations were performed to assess study aims. Overall, 63 children had 450 serum tobramycin concentrations. A one-compartment popPK model, including age, weight, a renal maturation model, and estimated glomerular filtration rate as covariates, was developed. With standard dosing, 1/3 of children achieved the target AUC_24,ss with younger children (<2 years) having the lowest probability of target attainment (PTA) (15%). The optimized dosing regimen improved target attainment in all children, increasing the PTA in children <2 years to 62%. CFTR modulator drugs did not affect tobramycin PK. Standard tobramycin dosing in children with CF achieves poor attainment of target serum AUC_24,ss, particularly in children <2 years. A fully individualized approach (available at https://www.kidscalc.org/) improved target attainment in all children. CFTR modulators had a negligible effect on tobramycin PK.