Therapeutic drug monitoring of vancomycin in neonatal and pediatric populations - identification of covariates for the development of model-informed precision dosing.

• Grant number: 25/13451-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Jhohann Richard de Lima Benzi
• Grantee: Bianca Tiemi Kuraoka Uemura
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Vancomycin (VAN) is a widely used antimicrobial agent in hospital settings for the treatment of sepsis. Although it has been studied for over 60 years, a consensus on serum monitoring in neonatal and pediatric populations was only published in 2020. However, the recommended therapeutic target of the area under the concentration-time curve over 24 hours divided by the minimum inhibitory concentration (AUC0-24h/MIC) between 400 and 600 mg·h/L was based on studies conducted in adults, as robust evidence in neonatal and pediatric populations is still lacking. Optimizing VAN therapy in these populations is further challenged by significant inter- and intra-individual pharmacokinetic variability, driven by extensive physiological changes that occur from birth through adolescence. Moreover, sepsis-associated alterations contribute additional variability, which may lead to subtherapeutic or toxic plasma concentrations depending on the magnitude and combination of these factors. Therefore, a generalized dosing recommendation for all populations and clinical scenarios does not reflect the complexity of septic conditions-particularly in critically ill patients-and is especially inadequate for special populations such as neonates and children. In this context, new approaches are needed to develop evidence-based dosing guidelines for children, considering developmental changes that affect pharmacokinetics (PK) and pharmacodynamics (PD). Population pharmacokinetic modeling (PopPK) has emerged as a promising tool to understand and predict drug behavior in different populations by incorporating individual variability through demographic, clinical, and laboratory covariates. This project aims to evaluate demographic, clinical (related to diagnosis and clinical course), laboratory, and pharmacotherapeutic variables to support the development of a population pharmacokinetic-pharmacodynamic (PopPK-PD) model. To this end, a retrospective, observational, multicenter study is planned, to be conducted in two secondary and tertiary hospitals in São Paulo, covering the period from January 2014 to June 2024. All patients who received VAN and underwent therapeutic drug monitoring with measured plasma concentrations will be included. Pharmacokinetic parameters will be estimated using PKanalix 2023R1. The normality of parameters will be assessed using the Shapiro-Wilk test. Correlations between PK parameters and quantitative covariates will be analyzed using Spearman's or Pearson's correlation tests, while qualitative covariates will be analyzed using the Chi-square test. Statistical analysis will be performed using GraphPad Instat®, with significance set at 5%. The study will enable the characterization of patients from the target populations who received VAN and underwent therapeutic drug monitoring, the collection of VAN pharmacokinetic data, and their associations with demographic, clinical, and laboratory information. These results will inform the development of a PopPK-PD model aimed at describing and simulating VAN plasma concentrations in the studied populations, with the goal of predicting dosing regimens and enabling individualized therapy. (AU)