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 0.7-3.7kg, 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 (V(d) ) 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 V(d) of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7kg) were estimated to be 0.066lh(-1) kg(-1) (95% CI 0.059, 0.073lh(-1) kg(-1) ) and 0.572lkg(-1) (95% CI 0.505, 0.639lkg(-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 V(d) . 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.

Figure 1

Population predicted and individual predicted concentrations of vancomycin vs. observed concentrations corresponding to the final model. Solid line is the line of identity

Figure 2

Visual predictive check of the final model for vancomycin. Symbols are the observed concentrations and the horizontal lines indicate the median and percentiles (5th, 25th, 75th and 95th) of vancomycin concentrations simulated with the final model. The intervals P₅-P₉₅ and P₂₅-P₇₅ cover the 90% and 50% predicted concentrations, respectively

Figure 3

Model-predicted concentrations of vancomycin (solid line) for a typical individual in this study (PMA = 34.6 weeks, weight = 1.7 kg) dosed according to Table 5 (12.5 mg kg⁻¹ every 12 h by means of a constant-rate infusion over 1 h). Symbols indicate predicted concentrations at sampling times used for determining C_min values (immediately before the start of a vancomycin administration) or C_max values (3 h after completion of drug infusion). The envelop represents the 90% prediction interval