Mechanistic PBPK–PD Modeling of Gentamicin: Impact of Renal Function and Age on Drug Exposure and Antibacterial Response

Abstract

Background: Gentamicin is a concentration-dependent aminoglycoside antibiotic with pharmacokinetics strongly influenced by renal function. Understanding its pharmacokinetic–pharmacodynamic (PK–PD) behavior across different physiological populations is essential for optimizing therapy.
Methods: A mechanistic PK–PD model was developed by integrating physiologically based pharmacokinetic (PBPK) modeling in PK-Sim with pharmacodynamic modeling in MoBi. A base model was established in a healthy adult population and extended to geriatric, chronic kidney disease (CKD), and combined CKD–geriatric populations by modifying physiological parameters. Plasma concentration–time profiles were linked to a bacterial growth–kill model to simulate pharmacodynamic response.
Results: The model reproduced the expected pharmacokinetic profile of gentamicin, characterized by rapid peak concentration followed by progressive decline. Differences in drug disposition were observed across populations, with slower decline in plasma concentrations in geriatric and CKD groups. These variations were reflected in pharmacodynamic outcomes, where bacterial suppression was prolonged and regrowth delayed in populations with reduced elimination. The most extended bacterial suppression was observed in the CKD–geriatric population.
Conclusion: The integrated PBPK–PD model demonstrates a clear relationship between gentamicin exposure and bacterial response across physiological conditions. The findings highlight the influence of renal function and age on drug behavior and provide a mechanistic framework for evaluating PK–PD relationships and supporting simulation-based dose optimization.