Assessment of cefepime toxico-dynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines.

Abstract Background Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets. Methods Data of CIN incidence and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime Cmin, Cmax and AUC24. The ability of each pharmacokinetic parameter to predict CIN was evaluated using Receiver-Operator Characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold. Results 102 cefepime courses were evaluated with CIN reported in 10. ROC analyses demonstrated all cefepime pharmacokinetic parameters were strongly predictive of CIN. Cmin of 49mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95%CI 0.758 – 0.999, p Conclusions The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with a Cmin of 49mg/L the most appropriate toxicity threshold. Further research is required to optimise cefepime dosing in the context of this therapeutic target.