Abstract
Background and Objective
For patients with intracranial infection, local intrathecal administration of meropenem may be a useful method to obtain a sufficient drug concentration in the cerebral spinal fluid (CSF). However, a large inter-individual variability may pose treatment efficacy at risk. This study aimed to identify factors affecting drug concentration in the CSF using population pharmacokinetics method.
Methods
After craniotomy, aneurysm patients with an indwelling lumbar cistern drainage tube who received a combined intravenous and intrathecal administration of meropenem for the treatment of suspected intracranial infection were enrolled. Venous blood and CSF specimens were collected for determining meropenem concentrations. Nonlinear mixed-effects modeling method was used to fit blood and CSF concentrations simultaneously and to develop the population pharmacokinetic model. The proposed model was applied to simulate dosage regimens.
Results
A three-compartmental model was established to describe meropenem in vivo behavior. Lumbar CSF drainage resulted in a drug loss, and drug clearance in CSF (CLCSF) was employed to describe this. The covariate analysis found that the drainage volume (mL/day) was strongly associated with CLCSF, and the effect of creatinine clearance was significant on the clearance of meropenem in blood (CL). Visual predictive check suggested that the proposed pharmacokinetic model agreed well with the observations. Simulation showed that both intravenous and intrathecal doses should be increased with the increases of minimum inhibitory concentration and daily CSF drainage volume.
Conclusion
This model incorporates covariates of the creatinine clearance and the drainage volume, and a simple to use dosage regimen table was created to guide clinicians with meropenem dosing.
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Acknowledgements
We would like to thank Dr. Yuanxing Wu and Dr. Guangqiang Chen for their help with sample collection.
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Funding
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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XL, SS, QW and ZZ have no conflict of interest to declare.
Ethics approval
All procedures in this study were in accordance with the 2008 Declaration of Helsinki and ICH Guideline for Good Clinical Practice. This protocol was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (ID: KY2014-014-02).
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Written informed consents from all patients or their healthcare surrogates were obtained.
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Li, X., Sun, S., Wang, Q. et al. Population Pharmacokinetics of Combined Intravenous and Local Intrathecal Administration of Meropenem in Aneurysm Patients with Suspected Intracranial Infections After Craniotomy. Eur J Drug Metab Pharmacokinet 43, 45–53 (2018). https://doi.org/10.1007/s13318-017-0422-1
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DOI: https://doi.org/10.1007/s13318-017-0422-1