Population Pharmacokinetic Analysis and Dose Regimen Optimization in Japanese Infants with an Extremely Low Birth Weight

Abstract

Vancomycin is a synthetic antibiotic effective against gram-positive pathogens. Although the clinical applicability of vancomycin for infants has been increasing, the pharmacokinetic data of vancomycin in extremely low-birth-weight infants are limited. The aim of this study was to construct a population pharmacokinetics model for vancomycin in extremely low-birth-weight infants and establish an optimal dosage regimen. We enrolled children aged less than 1 yr with a birth weight of less than 1000 g and body weight at vancomycin prescription of less than 1500 g. Pharmacokinetic data from 19 patients were analyzed and a population pharmacokinetics model was developed using nonlinear mixed-effects modeling software. Goodness-of-fit plots, a nonparametric bootstrap analysis, and a prediction-corrected visual predictive check were employed to evaluate the final model. The dosage regimen was optimized based on the final model. The pharmacokinetic data fit a one-compartment model with first-order elimination, and body weight and estimated serum creatinine level were used as significant covariates. In a simulation using the final model, the optimal dosage regimen, especially when the serum creatinine level (>0.6 mg/dL) was high, was 5.0–7.5 mg/kg twice a day every 12 h; this was required to reduce the dosage compared with that in previous studies. The recommended doses based on the current target time-course concentration curves may not be appropriate for extremely low-birth-weight infants.