Sepsis
Conditions
Keywords
beta-lactam, pharmacokinetics
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.
Interventions
DRUGImipenem-relebactam
After receipt of imipenem-relebactam, participants will have six blood samples collected over 6 hours for determination of imipenem and relebactam concentrations.
Sponsors
Merck Sharp & Dohme LLC
Hartford Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 54 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Imipenem 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] | The clearance in liters/hour of imipenem from the plasma of critically ill patients with augmented renal clearance |
| Relebactam 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] | The clearance in liters/hour of relebactam from the plasma of critically ill patients with augmented renal clearance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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] | The AUC in milligram\*hour/liter of imipenem calculated from concentrations collected between zero-6 hours and then extrapolated to infinity |
| 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] | The AUC in milligram\*hour/liter of relebactam calculated from concentrations collected between zero-6 hours and then extrapolated to infinity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Imipenem-Relebactam Participants will receive a single dose of intravenous imipenem-relebactam (500mg-250mg) as a 30 minute infusion.
Imipenem-relebactam: After receipt of imipenem-relebactam, participants will have six blood samples collected over 6 hours for determination of imipenem and relebactam concentrations. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Imipenem-Relebactam |
|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 14 |
| Albumin | 2.8 mg/dL STANDARD_DEVIATION 0.6 |
| APACHE II Score | 16 scores on a scale STANDARD_DEVIATION 6 |
| Cockcroft-Gault CrCL | 193 mL/min STANDARD_DEVIATION 62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 5 Participants |
| Total Body Weight | 89 kg STANDARD_DEVIATION 16 |
| Urine Measured CrCL | 156 mL/min STANDARD_DEVIATION 37 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 1 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Imipenem Clearance
The clearance in liters/hour of imipenem from the plasma of critically ill patients with augmented renal clearance
Time frame: 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]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Relebactam | Imipenem Clearance | 17.31 L/h | Standard Deviation 5.67 |
Primary
Relebactam Clearance
The clearance in liters/hour of relebactam from the plasma of critically ill patients with augmented renal clearance
Time frame: 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]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Relebactam | Relebactam Clearance | 11.51 L/h | Standard Deviation 4.79 |
Secondary
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
Time frame: 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]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Relebactam | Imipenem Area Under the Curve (AUC) | 32.33 mg*h/L | Standard Deviation 11.6 |
Secondary
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
Time frame: 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]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Relebactam | Relebactam Area Under the Curve (AUC) | 25.54 mg*h/L | Standard Deviation 10.21 |