Imipenem/Cilastatin/Relebactam PK in ECMO

Pharmacokinetics of Imipenem/Cilastatin/Relebactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)

Extracorporeal membrane oxygenation (ECMO) is a from of cardiopulmonary life-support for critically ill patients where blood is extracted from the vascular system and circulated by a mechanical pump while it is oxygenated and re-infused into the patient's circulation. It is well known that critically ill patients may experience alterations in antibiotic pharmacokinetics, and as a result, dosing modifications are generally required. There is a need to understand how ECMO circuits affect the pharmacokinetics and disposition of drugs. This study is designed to assess the pharmacokinetics of the new broad-spectrum antibiotic, imipenem-cilastatin-relebactam, in critically ill patients receiving ECMO.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Imipenem, Cilastatin and Relebactam

Detailed Description

This is a single center, open-label study to determine imipenem-cilastatin-relebactam pharmacokinetics in critically ill patients receiving ECMO. Eight patients with suspected suspected sepsis and who are receiving ECMO will be enrolled. Each participant will receive four to six doses of imipenem-cilastatin-relebactam according to current approved prescribing information, followed by ten blood samples to determine concentrations. Non-compartmental and population pharmacokinetic analyses will be determined to assess the effects of ECMO on imipenem and relebactam pharmacokinetic parameters.

• Study Type: Interventional
• Enrollment (Actual): 8
• 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: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 years or older;
• On support with Veno-venous- or Veno-arterial-ECMO;

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

  • Documented fever (oral, rectal, tympanic, or core temperature > 38.5° C)
  • Hypothermia (oral, rectal, tympanic, or core temperature < 35.0° C)
  • 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 agent (a history of mild rash to a β-lactam followed by uneventful re-exposure is not a contraindication);
• Severe renal dysfunction defined as a creatinine clearance < 15 mL/min (calculated by the Cockcroft-Gault equation using actual body weight) or requirement for continuous renal replacement therapy or hemodialysis;
• Hemoglobin less than 8 mg/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-Cilastatin-Relebactam; Participants will receive a four to six doses of intravenous imipenem-cilastatin-relebactam as per current prescribing information based on estimated creatinine clearance.	Drug: Imipenem, Cilastatin and Relebactam; After receipt of imipenem-cilastatin-relebactam, ten blood samples will be collected to determine the pharmacokinetics of imipenem and relebactam.; Other Names: Recarbrio

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 receiving ECMO.	6 hours (samples collected before the first imipenem/cilastatin/relebactam dose (i.e., blank), and at 0.5 and 6 hours following the first dose, and then at 0, 0.5, 0.75, 1, 2, 4, 5, and 6 hours after the start of the final dose).
Relebactam Clearance	The clearance in liters/hour of relebactam from the plasma of critically ill patients receiving ECMO.	6 hours (samples collected before the first imipenem/cilastatin/relebactam dose (i.e., blank), and at 0.5 and 6 hours following the first dose, and then at 0, 0.5, 0.75, 1, 2, 4, 5, and 6 hours after the start of the final dose).

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 and 6 hours at steady-state	6 hours (samples collected before the first imipenem/cilastatin/relebactam dose (i.e., blank), and at 0.5 and 6 hours following the first dose, and then at 0, 0.5, 0.75, 1, 2, 4, 5, and 6 hours after the start of the final dose).
Relebactam Area Under the Curve (AUC)	The AUC in milligram*hour/liter of relebactam calculated from concentrations collected between zero and 6 hours at steady-state	6 hours (samples collected before the first imipenem/cilastatin/relebactam dose (i.e., blank), and at 0.5 and 6 hours following the first dose, and then at 0, 0.5, 0.75, 1, 2, 4, 5, and 6 hours after the start of the final dose).

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Actual): May 31, 2023
• Study Completion (Actual): June 30, 2023

Study Registration Dates

• First Submitted: July 27, 2020
• First Submitted That Met QC Criteria: July 27, 2020
• First Posted (Actual): July 30, 2020

Study Record Updates

• Last Update Posted (Actual): August 7, 2024
• Last Update Submitted That Met QC Criteria: August 1, 2024
• Last Verified: August 1, 2024

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; Protease Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Imipenem; Relebactam; Cilastatin
• Other Study ID Numbers: 59752

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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