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

Background: In 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. Objectives: This study sought to describe plasma and tissue pharmacokinetics and pharmacodynamics (PK/PD) of cefepime in rats experiencing neurotoxicity. Methods: Male 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). Results: Exposure estimation of cerebral cortex demonstrated a median (IQR) AUC0-24 and Cmax 0-24 of 181.8 (85.2-661.3) mg·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·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 approximately 17 mg/L in the hippocampus exhibited signs of neurotoxicity. A hippocampal cefepime concentration of 4.1 μg/100 mg brain tissue best described seizure stages >1 for cefepime-induced neurotoxicty. Conclusions: A cefepime plasma AUC0-24 of 28,000 mg·24h/L and hippocampal concentrations of 4.1 lower case Greek μg/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. ### Competing Interest Statement The authors have declared no competing interest.