Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Varying Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis [PublishAheadOfPrint]

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria including carbapenem-resistant strains. The aim of this study is to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with varying renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens, and to calculate the fraction of time during the dosing interval where the free drug concentration in plasma exceeds the minimum inhibitory concentration (MIC) (fT>MIC).

Population PK models were developed with three renal function markers; body-surface-area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance based on 2571 plasma concentration data from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and the disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fT>MIC values were more than 75% in all patients (100% in most patients), suggesting a sufficient exposure to cefiderocol was provided by the tested dose regimen (2 g q8hr as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.

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