Optimization of Vancomycin Initial Dosing Regimen in Neonates Using an Externally Evaluated Population...

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Neonatal Pharmacology
• Antibiotic Dosing Optimization

Background:

• Revised vancomycin therapeutic monitoring guidelines (March 2020) recommend a population pharmacokinetics-guided Bayesian approach.
• The new guidelines favor estimating the 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio over trough concentrations.
• This study addresses the need to adapt vancomycin dosing strategies for neonatal patients in accordance with updated guidelines.

Purpose of the Study:

• To evaluate existing vancomycin population pharmacokinetic models using an external neonatal dataset.
• To select the most predictive model for optimizing vancomycin dosing in neonates.
• To develop a novel initial vancomycin dosing regimen based on the selected model.

Main Methods:

• Literature search for published vancomycin population pharmacokinetic models.
• External validation using a retrospective dataset of Canadian neonatal vancomycin concentrations.
• Assessment of model predictive performance using prediction and simulation diagnostics.
• Monte Carlo simulations to determine the optimal initial dosing regimen for maximizing therapeutic target attainment.

Main Results:

• Evaluated 28 vancomycin population pharmacokinetic models using 144 concentrations from 63 neonates.
• Identified 5 predictive models with bias ≤15% and imprecision ≤30%.
• The Grimsley and Thomson model demonstrated superior performance (bias -0.8%, imprecision 20.9%) and was selected for simulations.
• A novel initial dosing regimen of 15 mg/kg followed by 11 mg/kg every 8 hours was proposed.

Conclusions:

• An externally validated, predictive vancomycin population pharmacokinetic model was identified.
• A new initial vancomycin dosing regimen was developed to enhance therapeutic target attainment in neonates.
• Model-based dosing tools can assist clinicians in selecting appropriate initial vancomycin doses, potentially improving clinical outcomes.