Cefiderocol Pharmacokinetics in Adult Patients With Cystic Fibrosis

Population Pharmacokinetics of Cefiderocol During Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis

There is established evidence that adult patients with Cystic Fibrosis (CF) may have altered antibiotic pharmacokinetics compared with non-CF patients. Cefiderocol is a newly approved broad spectrum intravenous siderophore cephalosporin antibiotic, which has potent in vitro activity against multidrug resistant Pseudomonas aeruginosa, Burkholderia cepacia complex, Achromobacter species, and Stenotrophomonas maltophilia, all pathogens implicated in CF pulmonary exacerbations. This study will determine the pharmacokinetics and tolerability of cefiderocol in 12 adult CF patients admitted for a pulmonary exacerbation at one of 4 participating hospitals in the US. Patients will remain on standard of care IV antibiotics and receive 4-6 doses of cefiderocol 2 grams infused over 3 hours every 6-8 hours, depending on kidney function. Blood will be sampled after the final dose to determine concentrations and pharmacokinetics of cefiderocol. Safety and tolerability will be assessed throughout the 2 day study.

Study Overview

• Status: Completed
• Conditions: Pneumonia, Bacterial; Cystic Fibrosis
• Intervention / Treatment: Drug: Cefiderocol

Detailed Description

Participants will receive 4-6 doses of cefiderocol 2 grams every 6-8 hours, in addition to standard intravenous antibiotic therapy selected by the site. Just prior and then after the final dose, a total of nine blood samples will be collected to measure cefiderocol concentrations. Data will be fit to a population pharmacokinetic model. The final model will be utilized in a Monte Carlo simulation to determine the probability of several different dosing regimens retaining concentrations above the minimum inhibitory concentration (MIC) for at least 75% of the dosing interval. These data will be utilized to determine an optimized dosing regimen for adults with CF.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Hartford Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • IU Health University Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Clements University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documented diagnosis of CF
• Acute pulmonary exacerbation as the primary reason for admission to the hospital with requirement to receive systemic antibiotic treatment

Exclusion Criteria:

• Females that are pregnant and/or breastfeeding
• History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibiotic (a history of mild rash to a cephalosporin followed by uneventful re-exposure is not a contraindication)
• History of a lung transplant at any time in the past or any other organ transplantation (e.g., liver) within the last 6 months
• Moderate to severe renal dysfunction defined as a creatinine clearance < 60 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight) or requirement for continuous renal replacement therapy or hemodialysis
• A hemoglobin less than 8 gm/dL at baseline
• Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the investigator)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cefiderocol; Participants will receive intravenous cefiderocol at a dosing regimen consistent with the current prescribing information and according estimated renal function. Each dose will be infused over 3 hours.	Drug: Cefiderocol; Patients will receive intravenous cefiderocol every 6 to 8 hours for 4 to 6 doses.; Other Names: Fetroja

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clearance	This outcome determines the clearance of cefiderocol over the dosing interval.	0, 1.5, 3, 3.25, 4, 5, 6, and 8 hours after the final dose
Volume of Distribution	This outcome determines the volume of distribution of cefiderocol over the dosing interval.	0, 1.5, 3, 3.25, 4, 5, 6, and 8 hours after the final dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Probability of Target Attainment at 4 mcg/mL	This simulated outcome indicates the likelihood that cefiderocol will retain drug concentrations above the MIC for >/= 75% of the dosing interval at an MIC of 4 mcg/ml when administered as a 2g every 8 hour dose infused over 3 hour in patients up to a creatinine clearance of 120 ml/min. This analysis is conducted via a Monte Carlo simulation using the population pharmacokinetic parameter estimates and dispersion from the 12 participants who contributed pharmacokinetic data to the study	24 hours

Collaborators and Investigators

• Sponsor: Hartford Hospital
• Collaborators: University of Texas; Shionogi Inc.; University of Pittsburgh Medical Center; Indiana University Health Methodist Hospital; Keystone Bioanalytical, Inc.
• Investigators: Principal Investigator: Joseph L Kuti, PharmD, Hartford Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Actual): June 1, 2024
• Study Completion (Actual): December 11, 2024

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: March 29, 2022
• First Posted (Actual): April 6, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 12, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Pneumonia; Bacterial Infections; Bacterial Infections and Mycoses; Fibrosis; Cystic Fibrosis; Pneumonia, Bacterial; Beta Lactam Antibiotics; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Siderophores; Iron Chelating Agents; Cefiderocol
• Other Study ID Numbers: HHC-2022-0078

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No