A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid and Plasma Concentrations of Cefepime

Abstract

This study sought to define the transit of cefepime between plasma and cerebral spinal fluid (CSF) in a rat model. Male Sprague-Dawley rats received cefepime intravenously. A total daily dose of 150 mg/kg of body weight/day was administered as a single injection every 24 h for 4 days. Plasma samples were obtained via a second dedicated intravenous catheter. CSF sampling occurred via an intracisternal catheter. Cefepime levels in plasma and CSF were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic (PK) analyses were conducted using Pmetrics for R. PK parameters and exposures during the first 24 h (i.e., area under the concentration-time curve from 0 to 24 h [AUC_0-24] and maximum concentration of drug in serum from 0 to 24 h [C_{max 0-24}]) were calculated from Bayesian posteriors. CSF penetration was estimated by comparing the exposure profiles between plasma and the CSF. Eleven rats contributed PK data. A four-compartmental model with a lag compartment for CSF fit the data well for both plasma (Bayesian [R² = 0.956]) and CSF (Bayesian [R² = 0.565]). Median parameter values (with the coefficient of variation percentage [CV%] in parentheses) for the rate constants to CSF from the lag compartment (K₃₄), to the central compartment from the CSF compartment (K₄₁), and to the lag compartment from the central compartment (K₁₃) were 2.96 h^-1 (116.27%), 0.47 h^-1 (54.86%), and 0.13 h^-1 (23.42%), respectively. The elimination rate constant (k_el) was 3.15 h^-1 (7.5%). Exposure estimation revealed a plasma median (with interquartile range [IQR] in parentheses) half-life, AUC_0-24, and C_{max 0-24}, of 1.7 (1.5 to 1.9) h, 111.3 (95.7 to 136.5) mg · 24 h/liter, and 177.8 (169.7 to 236.4) μg/ml, from the first dose, respectively. Exposure estimation of CSF demonstrated a median (with IQR in parentheses) AUC_0-24 and C_{max 0-24} of 26.3 (16.6 to 43.1) mg · 24 h/liter and 6.8 (5.2 to 9.4) μg/ml, respectively. The median CSF/blood percentage of penetration was 19%. Cefepime transit to the CSF is rapid and predictable in the rat model. This model will be highly useful for understanding the therapeutic window for cefepime and neurotoxicity.IMPORTANCE This study defines the transit of cefepime between plasma and cerebral spinal fluid (CSF) in a rat model. Male Sprague-Dawley rats received cefepime intravenously. Plasma samples were obtained via a second dedicated intravenous catheter. CSF sampling occurred via an intracisternal catheter. Drug exposures and transfer from the plasma to the CSF during the first 24 h were calculated. The median CSF/blood percentage of penetration was 19%. Cefepime transit to the CSF is rapid and predictable in the rat model. This model will be highly useful for understanding the therapeutic window for cefepime and neurotoxicity.

Keywords: cefepime; cerebral spinal fluid; pharmacokinetics.