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.

Nao Kawaguchi,Takayuki Katsube,Toshihiro Wajima,Roger Echols

doi:10.1128/aac.01391-17

Abstract

ABSTRACTCefiderocol, 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.

Highlights

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains
The population PK models were developed using three renal function markers: (i) the estimated glomerular filtration rate, which was calculated by the modification of diet in renal disease (MDRD) equation [14] or an equation reported by Matsuo et al for Japanese subjects [15]; (ii) the eGFR converted by multiplying by the individual’s body surface area and dividing by 1.73 m2; and (iii) creatinine clearance (CLCR), which was calculated by the Cockcroft-Gault equation [16]
These three renal function markers were assessed separately in the population PK analysis because they have been used as renal function markers [14, 17,18,19] and the selection of renal function markers might affect the prediction of cefiderocol PK. fTMIC was calculated on the basis of simulated steady-state plasma cefiderocol concentrations and the MICs of Gram-negative uropathogens detected in the complicated urinary tract infection (cUTI) study

Summary

Introduction

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 PK analysis based on the plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with cUTI or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens in a phase 2 study of cefiderocol for the treatment of cUTI [13] and to calculate the fTMIC. The population PK models were developed using three renal function markers: (i) the estimated glomerular filtration rate (eGFR), which was calculated by the modification of diet in renal disease (MDRD) equation [14] or an equation reported by Matsuo et al for Japanese subjects [15] (the body surface area-adjusted eGFR [eGFRadj]); (ii) the eGFR converted by multiplying by the individual’s body surface area and dividing by 1.73 m2 (absolute eGFR [eGFRabs]); and (iii) creatinine clearance (CLCR), which was calculated by the Cockcroft-Gault equation [16]. These three renal function markers were assessed separately in the population PK analysis because they have been used as renal function markers [14, 17,18,19] and the selection of renal function markers might affect the prediction of cefiderocol PK. fTMIC was calculated on the basis of simulated steady-state plasma cefiderocol concentrations and the MICs of Gram-negative uropathogens detected in the cUTI study

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Conclusion