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Growth and maturational changes have been identified as significant covariates in describing variability in clearance of renally excreted drugs such as vancomycin. Because of immaturity of clearance mechanisms, quantification of renal function in neonates is of importance. Several serum creatinine (SCr)-based renal function descriptors have been developed in adults and children, but none are selectively derived for neonates. This review summarizes development of the neonatal kidney and discusses assessment of the renal function regarding estimation of glomerular filtration rate using renal function descriptors. Furthermore, identification of the renal function descriptors that best describe the variability of vancomycin clearance was performed in a sample study of a septic neonatal cohort. Population pharmacokinetic models were developed applying a combination of age-weight, renal function descriptors, or SCr alone. In addition to age and weight, SCr or renal function descriptors significantly reduced variability of vancomycin clearance. The population pharmacokinetic models with Léger and modified Schwartz formulas were selected as the optimal final models, although the other renal function descriptors and SCr provided reasonably good fit to the data, suggesting further evaluation of the final models using external data sets and cross validation. The present study supports incorporation of renal function descriptors in the estimation of vancomycin clearance in neonates.