Physiologically-based pharmacokinetic modeling and dosing optimization of cefotaxime in preterm and term neonates

Cefotaxime is commonly used in treating bacterial infections in neonates. To characterize the pharmacokinetic process in neonates and evaluate different recommended dosing schedules of cefotaxime, a physiologically-based pharmacokinetic (PBPK) model of cefotaxime was established in adults and scaled to neonates.A whole-body PBPK model was built in PK-SIM® software. Three elimination pathways are composed of enzymatic metabolism in the liver, passive filtration through glomerulus, and active tubular secretion mediated by renal transporters. The ontogeny information was applied to account for age-related changes in cefotaxime pharmacokinetics. The established models were verified with realistic clinical data in adults and pediatric populations. Simulations in neonates were conducted and 100% of the dosing interval where the unbound concentration in plasma was above the minimum inhibitory concentration (fT>MIC) was selected as the target index for dosing regimen evaluation.The developed PBPK models successfully described the pharmacokinetic process of cefotaxime in adults and were scaled to the pediatric population. Good verification results were achieved in both adults' and neonates' PBPK models, indicating a good predictive performance. The optimal dosage regimen of cefotaxime was proposed according to the postnatal age (PNA) and gestational age (GA) of neonates. For preterm neonates (GA < 36 weeks), dosages of 25 mg/kg every 8 hours in PNA 0-6 days and 25 mg/kg every 6 hours in PNA 7-28 days were suggested. For term neonates (GA ≥ 36 weeks), dosages of 33 mg/kg every 8 hours in PNA 0-6 days and 33 mg/kg every 6 hours in PNA 7-28 days were recommended.Our study may provide useful experience in practicing PBPK model-informed precision dosing in the pediatric population.