Imipenem-Relebactam Pharmacokinetics in Augmented Renal Clearance

NCT04147221 | Completed Phase 1 Results FDA Drug

• 1 other identifier: HHC-2019-0237
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Sepsis

Keywords

beta-lactam; pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• Imipenem Clearance

  The clearance in liters/hour of imipenem from the plasma of critically ill patients with augmented renal clearance

  6 hours [Timepoints taken at 0 hour (within 30 minutes prior to the start of infusion), 0.5 hours (end of infusion), 0.75, 1, 2, 4, and 6 hours after the start of the infusion]

• Relebactam Clearance

  The clearance in liters/hour of relebactam from the plasma of critically ill patients with augmented renal clearance

  6 hours [Timepoints taken at 0 hour (within 30 minutes prior to the start of infusion), 0.5 hours (end of infusion), 0.75, 1, 2, 4, and 6 hours after the start of the infusion]

Secondary Outcomes (2)

• Imipenem Area Under the Curve (AUC)

  6 hours [Timepoints taken at 0 hour (within 30 minutes prior to the start of infusion), 0.5 hours (end of infusion), 0.75, 1, 2, 4, and 6 hours after the start of the infusion]

• Relebactam Area Under the Curve (AUC)

  6 hours [Timepoints taken at 0 hour (within 30 minutes prior to the start of infusion), 0.5 hours (end of infusion), 0.75, 1, 2, 4, and 6 hours after the start of the infusion]

Study Arms (1)

Imipenem-Relebactam

EXPERIMENTAL

Participants will receive a single dose of intravenous imipenem-relebactam (500mg-250mg) as a 30 minute infusion.

Drug: Imipenem-relebactam

Interventions

Imipenem-relebactam DRUG

After receipt of imipenem-relebactam, participants will have six blood samples collected over 6 hours for determination of imipenem and relebactam concentrations.

Imipenem-Relebactam

Eligibility Criteria

• Age: 18 Years - 54 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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:
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hartford Hospital: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Hartford Hospital

Hartford, Connecticut, 06102, United States

Location

MeSH Terms

Conditions

Sepsis

Interventions

imipenem, cilastatin and relebactam

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Joseph L. Kuti
• Organization: Center for Anti Infective Research and Development

joseph.kuti@hhchealth.org

860-972-3612

Study Officials

• Joseph Kuti, PharmD

  Hartford Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2019
• First Posted: November 1, 2019
• Study Start: February 10, 2020
• Primary Completion: September 10, 2021
• Study Completion: September 19, 2021
• Last Updated: August 6, 2024
• Results First Posted: August 6, 2024

Record last verified: 2024-08

Locations

US (1)