Population Pharmacokinetics of Vancomycin in Premature Malaysian Neonates: Identification of Predictors for Dosing Determination in the First Month of Life

Background: Nothing is known of the pharmacokinetics of vancomycin in premature Malaysian infants during the first month of life. Knowledge of the factors which affect the fate of vancomycin in these infants could lead to improved dosage regimens for this antibiotic.

Methods: A one-compartment infusion model with first-order elimination was fitted to serum vancomycin concentration data (n=835 points) obtained retrospectively from the drug monitoring records of 116 premature, newborn infants. Vancomycin concentrations were estimated by florescence polarization immunoassay. Population and individual estimates of clearance and distribution volume and the factors which affected the variability of these parameters were obtained using the NONMEM 6 software. The predictive performance of the population model was evaluated by visual inspections of diagnostic plots and the robustness of the model was assessed by non-parametric bootstrapping with replacement. Dosing guidelines targeting AUC24/MIC ≥ 400 were explored using Monte Carlo simulation.

Results: Body size (weight), postmenstrual age and small-for-gestational-age are important factors explaining the between subject variability of vancomycin pharmacokinetic parameters in premature neonates. Infants who are small-for-gestational-age had a 20% reduction in vancomycin clearance compared to the appropriate-for-gestational-age control. Typical population parameter estimates of CL and V for a 1-kg premature neonate with a PMA of 30 weeks were 0.04256 L/h and 0.523 L, respectively. The estimated population vancomycin elimination half-life was 8.5 h. There was a 20% reduction in CL for SGA infants, compared to AGA infants. The BOV about CL was 16.7%. The visual inspections of diagnostic plots indicate acceptable predictive capability of the final model and the robustness of the model was found to be satisfactory from bootstrapping runs. Dosage regimens based on a priori target response values were formulated using model estimated pharmacokinetic parameters.

Conclusion: The pharmacokinetic parameters of vancomycin in premature Malaysian neonates were estimated. Improved dosage regimens based on a priori target response values were formulated by incorporating body size, PMA and SGA using Monte Carlo simulations with the model estimated pharmacokinetic parameters.