Abstract
Purpose
Combined intravenous and intraventricular administration of vancomycin into the cerebrospinal fluid (CSF) has been increasingly utilized for neurosurgical patients, but little is known about the population pharmacokinetics of vancomycin in the plasma and CSF. The aim of our study was to identify significant factors associated with plasma and CSF vancomycin concentrations to guide clinicians with vancomycin dosing.
Methods
Patients with an indwelling ventricular drainage catheter who received intravenous and intraventricular vancomycin were enrolled in this study. Blood and CSF samples were collected at scheduled times and vancomycin concentrations determined. A three-compartmental model (central, peripheral and CSF compartments) was proposed to describe the in vivo behavior of vancomycin. CSF outflow resulted in vancomycin loss, and the clearance of CSF compartment (CLCSF) was used to describe this loss. The nonlinear mixed-effects modeling method was applied to structure the population model, and the stepwise incorporation of seven covariates into the final model was attempted. Simulation was performed with the goal of CSF concentrations reaching or exceeding the minimum inhibitory concentration during therapy.
Results
Serum creatinine clearance had a significant influence on clearance of the central compartment. CLCSF had a positive correlation with drainage amount and a negative correlation with elapsed time. Model validation (bootstrap and visual predictive check) demonstrated the stability and performance of the proposed population model. A simple-to-use dosage regimen table was created based on the simulation results.
Conclusions
The proposed final model may be used to guide clinicians with vancomycin dosing in this specific patient population.
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Acknowledgements
The authors acknowledge Dr. Yuanxing Wu and Guangqiang Chen for their help with sample collection. This work was supported by grants from the National Natural Science Foundation of China (81503157), the Organization Department of Beijing Municipal Committee (2014000021469G258), and the Capital Medical University (16JL72).
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Q Wang and Z Zhao conceived and designed the study. X Li designed the statistical analysis and drafted the manuscript. X Li and S Sun performed the analysis and wrote the manuscript. X Ling and K Chen performed the experiments. Q Wang and Z Zhao supervised the quality of the study. All authors read and approved the final manuscript.
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Li, X., Sun, S., Ling, X. et al. Plasma and cerebrospinal fluid population pharmacokinetics of vancomycin in postoperative neurosurgical patients after combined intravenous and intraventricular administration. Eur J Clin Pharmacol 73, 1599–1607 (2017). https://doi.org/10.1007/s00228-017-2313-4
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DOI: https://doi.org/10.1007/s00228-017-2313-4