Background <p>Cefotaxime (CFT) is a broad spectrum, third-generation cephalosporin antibiotic prescribed for the treatment of severe infections, yet dosing guidelines for pediatric with renal impairment is scarce. The current study aimed to develop a physiological based pharmacokinetic (PBPK) model to characterize CFT disposition and model-based recommend dose adjustments in pediatrics with renal impairment. </p> Methods <p>Initially, the PBPK model of CFT was developed in adults with normal renal function before being scaled to pediatrics, considering age-related physiological changes using GastroPlus® software. Renal impairment was modelled through optimization of tubular secretion and glomerular filtration parameters based on observed data for both adults and pediatric populations.</p> Results <p>The model reasonably reproduced the observed pharmacokinetic profiles and showed acceptable agreement with the data (fold error ranges 0.84–1.37) or with renal impairment (fold error ranges 0.87–1.12). When compared to children with normal renal function, the predicted AUC0−∞ in children with renal impairment increased to 1.22- and 1.89-fold for moderate and severe renal impairment, respectively. Model-informed dose recommendations were 60% and 48% of the standard pediatric dose for moderate and severe renal impairment, respectively. </p> Conclusion <p>This PBPK framework supports rational, model-informed dosing of CFT in pediatric patients with varying renal impairment and supports dose recommendation development for high-risk populations.</p> Graphical abstract <p></p>