title: Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function.
abstract: Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear 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 MIC (Tf>MIC) for an 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 h with 3-h infusions provided >90% PTA for 75% Tf>MICfor an MIC of ≤4 μg/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was 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.
authors: Clinical Research Department, Shionogi & Co., Ltd., Osaka, Japan takayuki.katsube@shionogi.co.jp.
authors: Takayuki
authors: T
authors: Katsube
authors: Clinical Research Department, Shionogi & Co., Ltd., Osaka, Japan.
authors: Toshihiro
authors: T
authors: Wajima
authors: Clinical Research Department, Shionogi & Co., Ltd., Osaka, Japan.
authors: Toru
authors: T
authors: Ishibashi
authors: Shionogi Inc., Florham Park, New Jersey, USA.
authors: Juan Camilo
authors: JC
authors: Arjona Ferreira
authors: Shionogi Inc., Florham Park, New Jersey, USA.
authors: Roger
authors: R
authors: Echols
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000493:pharmacokinetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D006435:Renal Dialysis; D017262:Siderophores / Q000493:pharmacokinetics*; D000097602:Cefiderocol
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D017262:Siderophores; D000097602:Cefiderocol
keywords: cefiderocol; cephalosporin; dose adjustment; hemodialysis; modeling and simulation; pharmacodynamics; pharmacokinetics; population pharmacokinetics; renal function