Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment based on Renal Function [PublishAheadOfPrint]

The novel parenteral siderophore cephalosporin, cefiderocol, exhibits potent efficacy against most Gram-negative bacteria including carbapenem-resistant strains. Since cefiderocol is primarily excreted via the kidneys, this study was conducted to develop a population pharmacokinetic (PK) model to determine dose adjustment based on renal function.

Population PK models were developed based on cefiderocol concentration data in plasma, urine and dialysate with a non-linear mixed effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the minimum inhibitory concentration (MIC) (T_f>MIC) for a MIC range of 0.25 to 16 μg/mL. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function.

The developed models well described the PK of cefiderocol for each renal-function group. A dose of 2 g every 8 hours with 3-hr infusion provided >90% PTA for 75% T_f>MIC for an MIC of ≤4 μg/mL for patients with normal renal function, while a more frequent dose (every 6 hours) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval were selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis.

The PK of cefiderocol could be adequately modeled and the Modeling and Simulation approach suggested dose regimens based on renal function ensuring drug exposure with adequate bactericidal effect.

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