Background: For treatment of central nervous system infections caused by GNB, adequate cefepime concentrations are required in the cerebral spinal fluid (CSF) and brain. However, high plasma cefepime exposures have resulted in neurotoxicity. There is a need to understand the real-time pharmacokinetic (PK) relationship between plasma and CSF concentrations as serial CSF sampling is not regularly performed.
Methods: Male Sprague-Dawley rats received cefepime via an internal jugular vein catheter. A total daily dose of 150 mg/kg/day was administered as a single injection every 24 hours (h) for 4 days. Plasma samples (mean n=5 per rat) was obtained via a 2nd dedicated catheter, with up to 5 samples obtained on a single concentration time curve. CSF sampling occurred via an intracisternal catheter, with up to 2 samples taken every 24h. Cefepime in plasma and CSF was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. Multiple physiologic compartmental models were fit, with the ultimate model selected by Akaike score and rule of parsimony. Each rats concentrations were predicted from the final model, and predictive performance was evaluated with bias and imprecision of the population and Bayesian posterior prediction models. PK parameters were estimated, and PK exposures during the first 24h (i.e. AUC0-24, CMAX0-24, CMIN0-24) were calculated for each rat from Bayesian posteriors.
Results: Eleven rats contributed PK data. A 3-compartment model fit the data well [Figure 1: Plasma, Population (a) and Bayesian (b); Figure 2: CSF, Population (a) and Bayesian (b)]. Population median parameter values (CV%) for rate constant (Ke), volume central compartment (V1), volume CSF compartment (V3), rate to/from central/peripheral compartment (KCP, KPC), rate to/from central/CSF compartment (K13, K31) were: 5.04 h-1 (43.4%), 0.069 L (39.24%), 0.28 h-1 (52.11%), 17.42 h-1 (34.83%), 0.32 h-1 (165.3), 0.31h-1 (79.89), respectively. Non-compartmental analysis of the Bayesian posteriors revealed a plasma median half-life, AUC0-24, CMAX0-24, and CMIN0-24 of 2.6 hrs,158.1 mg*h/L, 189.3 mg/L, and 0.0003 mg/L from the first dose.
Conclusion: Cefepime transit to the CSF is rapid and highly predictable in the rat model. This model will be highly useful for understanding neurotoxicity outcomes for cefepime.
Grant fund from Merck
G. Pais, None
M. Joshi, None
N. J. Rhodes, None
M. H. Scheetz, None