Imipenem-Relebactam Pharmacokinetics in Augmented Renal Clearance

An Open-label Pharmacokinetic Study of Imipenem-Relebactam in Critically Ill Patients With Augmented Renal Clearance

Critically ill patients with sepsis undergo several physiological alterations that can alter the distribution, metabolism, and elimination of drugs. Some patients with sepsis may realize enhanced cardiac output leading to increases in glomerular filtration that result in increasing drug clearance. This clinical state is referred as Augmented Renal Clearance (ARC). Importantly, many beta-lactam antibiotics can be adversely affected by ARC, and some of these agents required increasing dosage to compensate for enhanced clearance. Imipenem-relebactam is a new broad spectrum antibiotic. This study is designed to assess the pharmacokinetics of both components, imipenem and relebactam, in critically ill patients with ARC.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Imipenem-relebactam

Detailed Description

This is a single center, open-label study to determine imipenem-relebactam pharmacokinetics in critically ill patients with Augmented Renal Clearance (ARC). Twelve patients with suspected ARC will be enrolled to ensure complete pharmacokinetic data in at least eight patients with confirmed ARC. Confirmation of ARC will be established by eight hour urine creatine determination. Each participant will receive a single dose of imipenem-relebactam (500mg/250mg) followed by six blood samples over a 6 hour interval to determine concentrations. Non-compartmental and population pharmacokinetic analyses will be determined to assess the effects of ARC on imipenem and relebactam pharmacokinetic parameters.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 54 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• APACHE II score > 12 and ≤ 35;
• Creatinine clearance (CrCL) ≥150 mL/min (as calculated by the Cockcroft-Gault equation using ideal or adjusted body weight) within 24 hours of dosing;

• Documented infection or presumed infection as confirmed by the presence of at least one of the following criteria within the past 72 hours:

  1. Documented fever (oral, rectal, tympanic, or core temperature > 38.5° C)
  2. Hypothermia (oral, rectal, tympanic, or core temperature < 35.0° C)
  3. An elevated white blood cell (WBC) count ≥ 12,000 cells/mm3

Exclusion Criteria:

• If female, currently pregnant or breast feeding;
• History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibiotic (Note: mild rash or erythema to penicillin or cephalosporin antibiotics would not disqualify a patient if they have received a carbapenem without problem);
• History of chronic kidney disease, hemodialysis, or peritoneal dialysis; or history of acute renal replacement therapy (e.g., hemodialysis, hemofiltration, hemodiafiltration) or extracorporeal membrane oxygenation (ECMO) associated with current illness;
• Suspected rhabdomyolysis or creatine kinase > 10,000 U/L;
• Any serum creatinine (SCr) before dosing that is increased ≥ 0.3 mg/dL from the baseline SCr used qualifying for enrollment;
• Urinary output <20 ml/hour for at least 2 hours (oliguria) within 24 hours before enrollment;
• Sustained (at least 1 hour) hypotension (systolic pressure < 90 mmHG or mean arterial pressure < 55 mmHg) refractory to vasopressors or intravenous fluid resuscitation for at least 24 hours before enrollment;
• Significant anemia defined as a hemoglobin < 8 g/dL at baseline;
• Use of probenecid, valproic acid, or imipenem within 3 days before study drug infusion;
• Acute liver injury, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of normal, or AST or ALT > 3 times the upper limit of normal with an associated total bilirubin > 2 times upper limit of normal;
• Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the investigator);
• Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of study data;
• Planned or prior participation in any other interventional drug study within 30 days.

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: Imipenem-Relebactam; Participants will receive a single dose of intravenous imipenem-relebactam (500mg-250mg) as a 30 minute infusion.	Drug: Imipenem-relebactam; After receipt of imipenem-relebactam, participants will have six blood samples collected over 6 hours for determination of imipenem and relebactam concentrations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imipenem Clearance	The clearance in liters/hour of imipenem from the plasma of critically ill patients with augmented renal clearance	6 hours
Relebactam Clearance	The clearance in liters/hour of relebactam from the plasma of critically ill patients with augmented renal clearance	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imipenem Area under the Curve (AUC)	The AUC in milligram*hour/liter of imipenem calculated from concentrations collected between zero-6 hours and then extrapolated to infinity	6 hours
Relebactam Area under the Curve (AUC)	The AUC in milligram*hour/liter of relebactam calculated from concentrations collected between zero-6 hours and then extrapolated to infinity	6 hours

Collaborators and Investigators

• Sponsor: Hartford Hospital
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Joseph Kuti, PharmD, Hartford Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2020
• Primary Completion (Actual): September 10, 2021
• Study Completion (Actual): September 19, 2021

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: October 30, 2019
• First Posted (Actual): November 1, 2019

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 29, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: pharmacokinetics; beta-lactam
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Imipenem; Relebactam
• Other Study ID Numbers: HHC-2019-0237

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No