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Introduction <p>Vancomycin is an antimicrobial agent for treating central nervous system (CNS) infections caused by Gram-positive bacteria. Due to practical and ethical reasons, it is difficult to evaluate vancomycin exposure in cerebrospinal fluid (CSF) and its relationship with therapeutic outcomes. Therefore, alternative methodologies are required. We developed a physiologically based pharmacokinetic (PBPK) model to characterize vancomycin exposure in plasma and CSF in patients with ventriculitis enrolled in a therapeutic drug monitoring program.</p> Methodology <p>PBPK modeling and simulation were conducted using PK-Sim® version 11.3. A PBPK model was constructed to simulate vancomycin exposure in plasma and CSF. Physicochemical parameters of vancomycin were incorporated into a large molecule model, and tissue distribution was described using the Rodgers-Rowland model.</p> Results <p>The final PBPK model incorporated vancomycin’s low brain permeability by adjusting the CSF-to-plasma partition coefficient to 0.17. Model validation was performed using data from 33 patients with ventriculitis under external ventricular drainage. The dosing regimen consisted of a 30&#xa0;mg/kg loading dose followed by a continuous intravenous infusion of 60&#xa0;mg/kg/day. Mean simulated vancomycin concentrations in plasma and CSF were 32&#xa0;mg/L and 7.2&#xa0;mg/L, respectively. The predicted CSF/plasma concentration ratio was 0.22, which closely matched the observed ratio of 0.17.</p> Conclusion <p>Vancomycin penetration into the CNS is low and variable, highlighting the importance of therapeutic drug monitoring and individualized therapy in patients with ventriculitis. In the future, this model may facilitate the selection of optimal dosing regimens by simulating alternative dosing strategies and establishing PK/PD relationships for CNS infections.</p>

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Assessment of Vancomycin Penetration into Cerebrospinal Fluid in Patients with Ventriculitis Using a Physiologically Based Pharmacokinetic Approach

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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  • Larissa Martins Alves Guimarães,
  • Letícia Oliveira de Vasconcellos Nacif,
  • Jhohann Richard de Lima Benzi,
  • Mayra Torres de Oliveira Santos,
  • Carolina Yamada,
  • Felipe Francisco Tuon,
  • João Paulo Telles,
  • Fernanda de Lima Moreira

摘要

Introduction

Vancomycin is an antimicrobial agent for treating central nervous system (CNS) infections caused by Gram-positive bacteria. Due to practical and ethical reasons, it is difficult to evaluate vancomycin exposure in cerebrospinal fluid (CSF) and its relationship with therapeutic outcomes. Therefore, alternative methodologies are required. We developed a physiologically based pharmacokinetic (PBPK) model to characterize vancomycin exposure in plasma and CSF in patients with ventriculitis enrolled in a therapeutic drug monitoring program.

Methodology

PBPK modeling and simulation were conducted using PK-Sim® version 11.3. A PBPK model was constructed to simulate vancomycin exposure in plasma and CSF. Physicochemical parameters of vancomycin were incorporated into a large molecule model, and tissue distribution was described using the Rodgers-Rowland model.

Results

The final PBPK model incorporated vancomycin’s low brain permeability by adjusting the CSF-to-plasma partition coefficient to 0.17. Model validation was performed using data from 33 patients with ventriculitis under external ventricular drainage. The dosing regimen consisted of a 30 mg/kg loading dose followed by a continuous intravenous infusion of 60 mg/kg/day. Mean simulated vancomycin concentrations in plasma and CSF were 32 mg/L and 7.2 mg/L, respectively. The predicted CSF/plasma concentration ratio was 0.22, which closely matched the observed ratio of 0.17.

Conclusion

Vancomycin penetration into the CNS is low and variable, highlighting the importance of therapeutic drug monitoring and individualized therapy in patients with ventriculitis. In the future, this model may facilitate the selection of optimal dosing regimens by simulating alternative dosing strategies and establishing PK/PD relationships for CNS infections.