Imipenem-Relebactam Pharmacokinetics in Augmented Renal Clearance

NCT ID: NCT04147221

Last Updated: 2024-08-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-10
• Study Completion Date: 2021-09-19

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.

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.

Conditions

Sepsis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Imipenem-Relebactam

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

Group Type: EXPERIMENTAL

Imipenem-relebactam

Intervention Type: DRUG

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

Interventions

Imipenem-relebactam

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

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 54 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Hartford Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joseph Kuti, PharmD

Role: PRINCIPAL_INVESTIGATOR

Hartford Hospital

Locations

Hartford Hospital

Hartford, Connecticut, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HHC-2019-0237

Identifier Type: -

Identifier Source: org_study_id