Dose Optimization of Cefazolin for Pediatric Patients with Renal Impairment Using Physiologically Based Pharmacokinetic Modeling (PBPK) in GastroPlus

Background/Objectives: Cefazolin is a first-generation cephalosporin antibiotic widely used for the treatment and prophylaxis of bacterial infections in both adult and pediatric populations. It is predominantly eliminated unchanged by the kidneys. Impaired renal function can reduce its clearance and increase systemic exposure. This study aimed to develop and validate a PBPK model of cefazolin using GastroPlus™ 9.9 to optimize dosing in pediatric patients with renal impairment. Methods: A cefazolin PBPK model incorporating renal transport processes was developed using clinical data from healthy adults, subsequently evaluated in adults with renal impairment, and scaled to healthy pediatrics following validation in these populations. The model was extrapolated to pediatric patients with varying degrees of renal impairment. Dose optimization was performed based on predicted exposure, followed by pharmacodynamic evaluation using unbound fractions and a selected MIC of 4 µg/mL. Results: The model demonstrated good agreement between observed and predicted pharmacokinetic parameters including Cmax and AUC0-∞ across the evaluated populations. Dose reductions of approximately 43%, 80%, and 90% relative to the standard pediatric dose were identified in moderate RI, severe RI, and ESRD, respectively, together with interval extension. Predicted %fT > MIC was 55.5%, 58%, 83%, and 81% for mild RI, moderate RI, severe RI, and ESRD, respectively. For surgical prophylaxis, unbound cefazolin concentrations remained above the MIC for 4.5–38.8 h across the RI groups, supporting maintenance above the MIC during a simulated 4 h surgical period. Conclusions: The PBPK model adequately describes cefazolin pharmacokinetic in healthy adults, adults with CKD, and healthy pediatric subjects and provides a model-informed basis for dose and interval adjustment in pediatric RI. The proposed regimens are model-based extrapolations requiring clinical confirmation, especially because the pediatric RI model was not independently validated against observed pediatric RI data.