Population pharmacokinetic analysis of vancomycin in neonates. A new proposal of initial dosage guideline

Abstract

Aim: To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates. Methods: Using nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1-48.1 weeks and 0.7-3.7 kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (Vd) of vancomycin. Results: Weight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and Vd of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7 kg) were estimated to be 0.066 l h-1 kg-1 (95% CI 0.059, 0.073 l h-1 kg-1) and 0.572 l kg-1 (95% CI 0.505, 0.639 l kg-1), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n = 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations. Conclusions: Postmenstrual age, co-administration of amoxicillin-clavulanic acid and spironolactone have a significant effect on the weight-normalized CL and Vd. An initial dosage guideline for vancomycin is proposed for preterm and full-term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin. © 2010 The Authors British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.