Vancomycin dosing in neonates: enhancing outcomes using population pharmacokinetics and simulation.

Abstract

Introduction: Optimizing vancomycin dosing in neonates is a critical yet complex goal. Traditional trough concentration-based dosing strategies correlate poorly with therapeutic efficacy and often fail to account for the significant renal function variability and drug clearance in neonates. The 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC₂₄/MIC) ≥ 400 mg h/L has emerged as a superior pharmacodynamic target. Population pharmacokinetics (PopPK) models allow optimized dosing by incorporating neonatal-specific factors such as postmenstrual age (PMA), gestational age (GA), serum creatinine (SCr), and weight.

Objective: To develop optimized vancomycin dosing regimens for neonates that achieve an 80% probability of target attainment (PTA) for an AUC₂₄/MIC ≥ 400 mg h/L across diverse clinical cohorts and simulated neonatal populations.

Methods: Real-world data from three international centers (Belgium, New Zealand, USA), including 610 individuals and 2399 vancomycin concentrations, were used to externally evaluate a previously published PopPK model (NONMEM^®). Missing data, including body weight, were imputed using Amelia II version 1.7.3 for R, while Zelig for R integrated multiple imputed datasets. A virtual population of 10,000 neonates was independently generated using MATLAB to simulate clinical scenarios considering covariates such as PMA, GA, SCr, body weight, and imputed body length.

Results: Simulations showed that PMA and SCr were key covariates that significantly improved PTA, particularly in preterm neonates. Preterm neonates achieved PTAs of 80% with daily doses of 30 or 40 mg/kg/day, while term neonates required 15 mg/kg every 8 hours or 20 mg/kg every 12 hours. The simulations demonstrated that these optimized dosing strategies achieved an 80% PTA for AUC₂₄/MIC ≥ 400 mg h/L in the virtual neonatal population. For neonates with PMA < 29 weeks and SCr > 0.6 mg/dL, including SCr as a covariate increased the likelihood of achieving the target from 65% to 87%.

Conclusion: Incorporating developmental factors like PMA and SCr into vancomycin dosing strategies achieved robust and clinically relevant outcomes. The optimized regimens achieved an 80% PTA for the AUC₂₄/MIC target for preterm and term neonates. These findings offer a scalable framework for improving neonatal vancomycin pharmacotherapy across diverse populations and clinical settings.