Vancomycin Dosing in Neonates: Enhancing Outcomes Using Population Pharmacokinetics and Simulation

Sílvia M Illamola¹Jiraganya (JJ) Bhongsatiern^2,3Angela Birnbaum^1,4Shaun S Kumar⁵Josh Courter⁶David B Heslam⁷Karel Allegaert^10,8,9David M Reith¹¹Pankaj Desai³Catherine M T Sherwin^{1,12,13,14,4*}

• ¹Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States
• ²Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States
• ³Department of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, United States
• ⁴Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, The University of Utah, Salt Lake City, Utah, United States
• ⁵Parexel International, Sydney, Australia
• ⁶Pharmacy, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
• ⁷Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
• ⁸Department of Pharmaceutical and Pharmacological Sciences, Faculty of Medicine, KU Leuven, Leuven, Belgium
• ⁹Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Flemish Brabant, Belgium
• ¹⁰Department of Pharmacy, Erasmus Medical Center, Rotterdam, Netherlands
• ¹¹Office of the Dean, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
• ¹²Internal Medicine, UWA Medical School, University of Western Australia, Perth, Utah, Australia
• ¹³Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States
• ¹⁴Differentia Biotech Ltd, San Francisco, United States

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.