Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates

Abstract

Background: The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), varies between paediatric and adult patients.

Objective: The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen.

Methods: This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units. They all received vancomycin 15 mg/kg every 12 h. Blood was sampled just before administration of the third, sixth and ninth vancomycin dose. Pharmacokinetic parameters were estimated using a Bayesian approach implemented in Monolix 2018R2 software. Covariates assessed included postmenstrual age, current weight, creatinine clearance, albumin, gestational age, body surface area and current age. We used Monte Carlo simulations for dose regimen optimisation targeting area under the concentration-time curve up to 24 h (AUC_0-24h) of ≥ 400 mg × h/L.

Results: In total, 19 preterm neonates were enrolled in the study with a median age of 14 (3-58) days. A one-compartment model with linear elimination best described the pharmacokinetics of vancomycin. Volume of distribution and clearance was 0.88 L and 0.1 L/h, respectively, for a typical neonate weighing 1.48 kg. Simulation of the current dose regimen showed that 27.5% of the neonates would achieve the target AUC_0-24h of ≥ 400 mg × h/L, and 70.7% of the neonates would achieve it with 12 mg/kg every 8 h.

Conclusion: The majority of the neonates were under dosed. Vancomycin 12 mg/kg should be administered every 8 h over 1 h infusion to improve the likelihood of achieving the AUC_0-24h target of ≥ 400 mg × h/L. This target is considered optimal for MRSA infections, where the vancomycin minimum inhibitory concentration is ≤ 1 µg/mL.

Fig. 1

Observed vancomycin concentrations over time

Fig. 2

Goodness-of-fit plots: population and individual predicted concentration versus time. Time and predicted concentration versus individual weighted residuals

Fig. 3

Visual predictive check for vancomycin for 1000 simulations of the final pharmacokinetic model. The upper, middle and lower solid lines represent the 95th, 50th and 5th percentiles, respectively; the dots represent observed trough concentrations

Fig. 4

The exposure (AUC_0-24h and C_max) profiles for the current and optimised vancomycin dose regimen. A dotted line on the AUC_0-24h axis represents the target AUC_0-24h; the two dotted lines on the C_max axis represent the upper and lower quartiles values of C_max associated with AUC_0-24h ≥400 mg × h/L. AUC_0-24h area under the concentration–time curve up to 24 h, C_max peak plasma concentration