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

Sean N. Avedissian, Gwendolyn Pais, Medha D. Joshi, Nathaniel J. Rhodes, Marc H. Scheetz

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Article numbere00595-18
JournalmSphere
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2019

Keywords

  • Cefepime
  • Cerebral spinal fluid
  • Pharmacokinetics

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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