Hippocampal Concentrations Drive Seizures in a Rat Model for Cefepime-induced Neurotoxicity

BackgroundIn high dose, cefepime causes neurotoxicity in patients with kidney injury; however, the relationship between exposure and observed neurotoxicity is not clear, and no animal model presently recapitulates the human condition. ObjectivesThis study sought to describe plasma and tissue pharmacokinetics and pharmacodynamics (PK/PD) of cefepime in rats experiencing neurotoxicity. MethodsMale Sprague-Dawley rats (n=21) received escalating cefepime total daily doses ranging from 531-1593 mg/kg body weight/day administered as a short infusion (0.5 mL/min) every 24h for 5 days. Cefepime was quantified in plasma, cerebral cortex and hippocampus via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple PK/PD models of cefepime transit between plasma and brain compartments (i.e. cerebral cortex and hippocampus) and neurotoxic response were explored using Monolix 2021R1 (LixoftPK). ResultsExposure estimation of cerebral cortex demonstrated a median (IQR) AUC0 -24 and Cmax 0 -24 of 181.8 (85.2-661.3) mg {middle dot} 24 h/liter and 13.9 (1.0-30.1) mg/L, respectively. The median cerebral cortex/blood percentage of penetration was 1.7%. Exposure estimation of hippocampus demonstrated a median (IQR) AUC0 -24 and Cmax 0 -24 of 291.4 (126.6-1091.6) mg {middle dot} 24 h/liter and 8.8 (3.4-33.4) mg/L, respectively. The median hippocampus/blood percentage of penetration was 4.5%. Rats that reached a cefepime Cmax of {square}17 mg/L in the hippocampus exhibited signs of neurotoxicity. A hippocampal cefepime concentration of 4.1 {micro}g/100 mg brain tissue best described seizure stages >1 for cefepime-induced neurotoxicty. ConclusionsA cefepime plasma AUC0 -24 of 28,000 mg*24h/L and hippocampal concentrations of 4.1 {micro}g/100 mg brain tissue may be a threshold for cefepime-induced neurotoxicity. This model provides a methodology for future interrogation of the relationship between plasma concentrations, brain tissue concentrations, and neurotoxicity.