Individualized Empiric Vancomycin Dosing in Neonates Using a Model-Based Approach

Abstract

Background: Vancomycin dosing in neonates is challenging because of the large variation in pharmacokinetics. Existing empiric dosing recommendations use table-based formats, within which a neonate is categorized on the basis of underlying characteristics. The ability to individualize dosing is limited because of the small number of "dose categories," and achieving narrow exposure targets is difficult. Our objective was to evaluate a model-based dosing approach (which we designated Neo-Vanco) designed to individualize empiric vancomycin dosing in neonates.

Methods: Neo-Vanco was developed on the basis of a published, externally validated population pharmacokinetic model. Using a simulation-based methodology, individualized empiric doses that maximize the probability of attaining a 24-hour area under the curve/minimum inhibitory concentration ratio (AUC24/MIC) of >400 while minimizing troughs >20 mg/L are calculated. To evaluate the Neo-Vanco strategy, retrospective data from neonates treated with vancomycin at 2 healthcare systems were used, and empiric dose recommendations from the following 4 sources were examined: Neo-Vanco, Neofax, Red Book, and Lexicomp. Predicted AUC24 and troughs were calculated and compared.

Results: Overall, 492 neonates were evaluated (median postmenstrual age, 36 weeks [5th-95th percentiles (90% range), 25-47 weeks]; median weight, 2.4 kg [90% range, 0.6-4.8 kg]). The percentage of neonates predicted to achieve an AUC24/MIC of >400 was 94% with Neo-Vanco, 18% with Neofax, 23% with Red Book, and 55% with Lexicomp (all P < .0001 vs Neo-Vanco). Predicted troughs of >20 mg/L were infrequent and similar across the dosing approaches (Neo-Vanco, 2.8%; Neofax, 1.0% [P = .03]; Red Book, 2.6% [P = .99]; and Lexicomp, 4.1% [P = .27].

Conclusion: A model-based dosing approach that individualizes empiric vancomycin dosing was predicted to improve achievement of target exposure levels in neonates. Prospective clinical evaluation is warranted.

Keywords: modeling and simulation; neonates; pharmacokinetics; vancomycin.