Najia Rahim 1, Muhammad Sarfraz, Muhammad Wahajuddin
1 Dow University Of Health Sciences (Karachi, Pakistan)
Introduction: Cefotaxime is a broad spectrum, third-generation cephalosporin antibiotic prescribed for the treatment of severe infections in pediatrics (1). Renal elimination of cefotaxime is via glomerular filtration and actively secretion by organic anion transporters (OATs) (2). Physiological changes associated with renal impairment (RI) influences the dosing of cefotaxime in adults and children (3-5). This is because RI leads to decreased clearance (CL), likely driven by reduced transporter activity (OAT1/3), leading to increased cefotaxime internal exposure and accumulation. It is recommended to reduce the cefotaxime dose in patients suffering from severe renal impairment (RI) based on creatinine clearance to avoid drug accumulation. However, dosage guidelines are limited for pediatrics with renal impairment. Physiological based pharmacokinetic (PBPK) modeling is increasingly recognized as a valuable tool for precision-dosing in pediatric populations with altered physiology associated with renal impairment (6, 7). A mechanistic PBPK model can characterize cefotaxime exposure across different pediatric populations with varying degree of renal impairment and support exposure-based dose adjustment, provided it is accurately developed and validated.
Method: The current study develop and validate a PBPK model for different pediatric age groups, incorporating developmental and pathophysiologoical changes associated with renal impairment using GastroPlusTM software. The PBPK model utilized to characterize cefotaxime disposition and recommend dose adjustments in pediatrics with renal impairment.
Initially, a PBPK model of cefotaxime was developed in adults with normal renal function before being scaled to pediatrics, considering age-related physiological changes using GastroPlus® software (8). Renal impairment was mechanistically implemented through optimization of tubular secretion and glomerular filtration parameters based on observed data for both adults and pediatric populations (3-5). By establishing and validating the PBPK models in adult and pediatric populations with impaired renal function, we predict the outcome of renal impairment on cefotaxime internal exposure and recommend the appropriate dosages for these populations. AUC0-α served as a predictive indicator of cefotaxime exposure in RI. Dosage optimization was performed using this parameter to meet the patient-specific features and age-specific target PK profiles.
Results: The adult model accurately predicted cefotaxime exposure (AUC0-α) in patients without renal impairment (fold error ranges 0.84-1.37) or with renal impairment (fold error ranges 0.87-1.12) (8-16). Pediatric PBPK model proved the prediction accuracy with fold error ranges in between 0.5 and 2 in children without renal impairment (17, 18). 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 (5).
In pediatric patients, model-informed dose reductions to 40%-73% of the standard adult dose is recommended, which achieved 52.5-77.5% T>MIC in these patients. The recommended cefotaxime dosages for pediatrics with moderate and severe RI were 35 mg/kg BW and 24 mg/kg BW, respectively. At these doses, simulation predicted attainment of pharmacodynamic targets, with 56.25% and 84.5% T>MIC for moderate and severe RI, assuming an 8-hour dosing interval and MIC values of 1-4 mg/L, respectively.
Conclusion: The current study has demonstrated the first application of PBPK modeling to cefotaxime dosage recommendations in a pediatric population with RI. These findings confirms the applicability of PBPK modeling in precision dosing of organic anion transporter (OAT) substrates in vulnerable pediatric populations. The developed model was validated to predict cefotaxime exposure in adults and pediatrics with or without RI by mechanistically accounting for changes in OAT transporter activity and GFR. The model-informed dose reduction was proposed for children with severe RI require a dose of 24 mg/kg BW, whereas those with moderate RI require 35 mg/kg BW. For all optimized cefotaxime dosages, the 56.25-84.5%T>MIC has been attained in pediatric populations with RI.
This mechanistic approach enables individualized dosing in pediatrics with renal impairment and favors broader adoption of model-informed precision dosing (19). This PBPK framework supports rational, model-informed dosing of renally cleared drugs in pediatric patients with varying renal impairment and illustrate the applicability of PBPK modeling to recommend dosing in high-risk populations (20).
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Reference: PAGE 34 (2026) Abstr 11921 [www.page-meeting.org/?abstract=11921]
Poster: Drug/Disease Modelling - Paediatrics