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

Antimicrob Agents Chemother. 2018 Jan 25;62(2):e01391-17. doi: 10.1128/AAC.01391-17. Print 2018 Feb.

Abstract

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of 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 the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and 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 fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.

Keywords: acute uncomplicated pyelonephritis; augmented renal function; cefiderocol; cephalosporin; complicated urinary tract infection; pharmacokinetics; population pharmacokinetics; renal function; siderophore.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Bacterial Agents / blood
  • Anti-Bacterial Agents / pharmacokinetics*
  • Body Weight / drug effects
  • Case-Control Studies
  • Cefiderocol
  • Cephalosporins / blood
  • Cephalosporins / pharmacokinetics*
  • Creatinine / blood
  • Drug Administration Schedule
  • Female
  • Glomerular Filtration Rate
  • Gram-Negative Bacterial Infections / blood
  • Gram-Negative Bacterial Infections / drug therapy*
  • Gram-Negative Bacterial Infections / microbiology
  • Gram-Negative Bacterial Infections / pathology
  • Humans
  • Male
  • Middle Aged
  • Models, Statistical
  • Pyelonephritis / blood
  • Pyelonephritis / drug therapy*
  • Pyelonephritis / microbiology
  • Pyelonephritis / pathology
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / microbiology
  • Renal Insufficiency, Chronic / pathology
  • Severity of Illness Index
  • Siderophores / blood
  • Siderophores / pharmacokinetics*
  • Urinary Tract Infections / blood
  • Urinary Tract Infections / drug therapy*
  • Urinary Tract Infections / microbiology
  • Urinary Tract Infections / pathology

Substances

  • Anti-Bacterial Agents
  • Cephalosporins
  • Siderophores
  • Creatinine