Study rationale

Gentamicin, an aminoglycoside antibiotic, is commonly used to treat neonatal and infant infections like sepsis, pneumonia, and urinary tract infections. However, dosing gentamicin in this age group is challenging due to rapid physiological changes in body composition and renal function. Gentamicin is hydrophilic and primarily eliminated by the kidneys, so these developmental changes in renal clearance directly affect drug exposure.

Clinically, the goal is to ensure sufficient exposure for efficacy while avoiding excessive levels that could lead to toxicity, particularly nephrotoxicity and ototoxicity. Despite consensus on once-daily dosing, there remains variation in guidelines, especially for neonates and young infants. The question addressed by this study was whether the current Dutch Paediatric Formulary (DPF) dosing recommendations  achieve efficacy targets while minimizing toxicity risk in term neonates and infants.

The role of PBPK modelling in supporting clinical decision-making

PBPK modelling was used in this study to simulate current DPF gentamicin dosing regimens. This allowed the prediction of plasma concentrations and systemic exposure across neonatal and infant age groups and assess whether the current recommendations met both therapeutic targets for efficacy and safety. PBPK modelling also enabled the evaluation of alternative dosing regimens.

A key advantage of PBPK modelling is its ability to simulate real-world physiological changes that affect drug metabolism, offering a more precise and age-appropriate dosing strategy than generalized guidelines. Additionally, the study considered clinical readiness by evaluating model uncertainty, the practicality of proposed dosing regimens, and the overall benefit-risk ratio, ensuring the results were suitable for implementation in clinical settings.

Evaluation of paediatric dosing

Simulations of the current DPF dosing regimen for neonates revealed that, while the peak concentrations generally fell within the desired therapeutic range, trough concentrations were often elevated, exceeding the safety threshold. This raised concerns about potential nephrotoxicity. Decreasing the dose was not considered appropriate, so extending the dosing interval was proposed, allowing for better drug clearance between doses.

For infants, the current dosing regimen was adequate for maintaining therapeutic levels, although for older infants (6–12 months), the C_max tended to be on the low end of the efficacy range. A slight increase in the dose was suggested to optimize peak levels without compromising safety. Overall, the benefit–risk balance of the optimized regimens was considered positive and suitable for clinical implementation.

PBPK modelling added clear value by quantitatively balancing efficacy and toxicity targets across rapidly changing developmental stages, enabling physiologically grounded, age-specific dosing recommendations.