Elevated hippocampal and cortical cefepime concentrations correlate with seizures in an acute kidney injury rat model

Cefepime is associated with neurotoxicity, particularly in the setting of renal impairment where drug exposure increases. This study evaluated cefepime concentrations in the brain tissue during neurotoxicity in a rat model of acute kidney injury (AKI). Male Sprague-Dawley rats (n = 18) received daily intravenous cefepime at 1,250 or 1,593 mg/kg for 5 days. Acute kidney injury was induced using folic acid (250 mg/kg on day 1, then 100 mg/kg/day prior to cefepime). Seizure activity was assessed using a modified Racine scale. Plasma samples were collected three to four times per day; the brain tissues (cerebral cortex and hippocampus) were collected at euthanasia. Cefepime concentrations were measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed using Monolix 2024R1. Rats with seizure scores >1 had significantly higher median cefepime levels in the cerebral cortex (64.2 vs 14.1 μg/g, P = 0.0014) and hippocampus (66.2 vs 15.0 μg/g, P < 0.0001). Median (IQR) estimated exposures in the cortex were AUC_0-24 = 565 (161.5-1,346) mg·h/L and C_max = 36.0 (16.3-75.6) mg/L, and in the hippocampus were AUC_0-24 = 694.8 (151.5-1,152) mg·h/L and C_max = 41.9 (13.7-62.8) mg/L. Neurotoxicity in the rat correlated with plasma AUC_0-24 > 30,000 mg·h/L and brain tissue concentration of approximately 40 mg/L. Neurotoxicity was achieved via intravenous dosing of cefepime in this rat model of acute kidney injury. Cefepime concentrations were higher in the cerebral cortex and hippocampal brain tissues in animals that had seizure stages >1.