Clinical trial NCT04147221: Imipenem-Relebactam Pharmacokinetics in Augmented Renal Clearance
Official title: An Open-label Pharmacokinetic Study of Imipenem-Relebactam in Critically Ill Patients With Augmented Renal Clearance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Sepsis
Keywords: beta-lactam
pharmacokinetics
Lead sponsor: Hartford Hospital
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2019-11-01
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 54
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

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.

Primary outcomes:
measure: Imipenem Clearance
timeFrame: 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]
measure: Relebactam Clearance
timeFrame: 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:
measure: Imipenem Area Under the Curve (AUC)
timeFrame: 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]
measure: Relebactam Area Under the Curve (AUC)
timeFrame: 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]
Other outcomes:
Locations:
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
Study officials:
affiliation: Hartford Hospital
name: Joseph Kuti, PharmD
role: PRINCIPAL_INVESTIGATOR
References: