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

Abstract

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.

Bibliographic Information