Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection

Abstract

Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gram-negative bacteria, including carbapenem-resistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 ml/min, and it is adjusted for patients with <60 ml/min or ≥120 ml/min CrCL. A population pharmacokinetic (PK) model was constructed using 3,427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors, including infection sites and mechanical ventilation, were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT_>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT_>MIC was >90% against MICs of ≤4 μg/ml for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients, including the patients with augmented renal function, ventilation, and/or severe illness.

Keywords: augmented renal function; bloodstream infections; cefiderocol; cephalosporin; complicated urinary tract infection; pharmacodynamics; pneumonia; population pharmacokinetics; ventilation.

FIG 1

Prediction-corrected visual predictive check for final model by study and renal function group. Results for 500 simulations. Renal function groups defined by CrCL were as follows: augmented, ≥120 ml/min; normal or mild, 60 to <120 ml/min; moderate, severe, or end-stage renal disease (ESRD), 5 to <60 ml/min. Semilog scale. Solid line, observed median; dashed line, observed 2.5th and 97.5th percentiles; dark-gray shaded area, model-predicted 95% confidence interval of median; gray shaded area, model predicted 95% confidence intervals of 2.5th and 97.5th percentiles.

FIG 2

Box plots for estimated C_max and daily AUC by infection site (A) and ventilation status in pneumonia patients (B). cUTI in CR, cUTI in CREDIBLE-CR study; cUTI in APEKS, cUTI/AUP in APEKS-cUTI study. Red circle, post hoc estimates of parameters for individual patients. Horizontal black center line represents median, with the top and the base of the boxes representing first and third quartiles (interquartile range [IQR]); whiskers represent the most extreme data within 1.5 times the IQR.

FIG 3

Relationships of %fT_>MIC with microbiological outcome, clinical outcome, or vital status in CREDIBLE-CR and APEKS-NP studies.

FIG 4

Integrated probability of target attainment for 75% fT_>MIC (A) and 100% fT_>MIC (B) calculated by weighting for distribution of creatinine clearance in phase 3 studies.