A translational pharmacokinetic rat model of cerebral spinal fluid and plasma concentrations of cefepime

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 fourcompartmental model with a lag compartment for CSF fit the data well for both plasma (Bayesian [R ² = 0.956]) and CSF (Bayesian [R ² = 0.565]). Median parameter values (with the coefficient of variation percentage [CV%] in parentheses) for the rate constants to CSF from the lag compartment (K ₃₄ ), to the central compartment from the CSF compartment (K ₄₁ ), and to the lag compartment from the central compartment (K ₁₃ ) 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.