Real-time pharmacokinetic measurements of vancomycin in the brain of mice via electrochemical aptamer-based sensors

Abstract

<b>Abstract ID 17697</b> <b>Poster Board 73</b> Disease treatment and prevention are currently based on population-averaged pharmacological data obtained from a limited number of patients. Additionally, clinical dose estimations are based on physical parameters like body mass, age, and pharmacogenetic markers that do not consider idiosyncratic or state-dependent variables (e.g., exercise, hydration, eating habits, etc.). As can be expected, these pharmacokinetic approximations can lead to large variability in efficacy for individual patients. Moreover, current methods for measuring drug plasma exposures require offline measurement of analytes and the actual site of action (e.g., the brain) is often completely inaccessible for measurements from awake behaving animals. Therefore, pharmacokinetic-pharmacodynamic correlations are often based on low-accuracy data. The latter is a common scenario in brain-related disease and injury treatment as there is limited information about drugs that permeate the blood-brain barrier (BBB) and even less regarding drug distribution across different brain regions. For example, the aminoglycoside vancomycin is a common antibiotic used in perioperative neurosurgery and the management of penetrating brain injury, and the standard of care requires its delivery via intravenous (I.V.) injection. Vancomycin has poor permeability across the BBB (CSF-to-plasma ratios of 0.07-0.30); therefore, high vancomycin intravenous dosing is required to achieve brain concentrations above minimum inhibitory concentrations. To our knowledge, however, there are no published reports showing measurable concentrations of vancomycin in the brain after intravenous administration. Consequently, prophylaxis dosing regimens remain highly speculative. Electrochemical aptamer-based (E-AB) sensors, an emerging technology in the field of pharmacology, have shown great success at measuring full pharmacokinetic profiles of small molecule drugs in-situ in the vein of rodents with unprecedented accuracy, precision and temporal resolution. The E-AB sensor platform is reagentless and has recently enabled the real-time tracking of vancomycin concentrations in the blood of rats. In this work, we expand the use of E-AB sensors to the measurement of vancomycin in the brain of mice. We demonstrate that following an I.V. injection of 75 mg/kg (tail vein bolus), the concentration of vancomycin reaches a C_max of 8 μM in the cortex in 1.5 h, plateauing at that level for the remaining of the experiment (∼2 h). To our knowledge this the first real-time in&nbsp;vivo measurement of vancomycin in the brain. Future experiments in this project will measure vancomycin concentrations in different brain regions following multiple I.V. doses and validate the concentration measurements using gold-standard mass spectrometry methods.