Sepsis
Conditions
Keywords
beta-lactam, pharmacokinetics
Brief summary
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.
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.
Interventions
DRUGImipenem, Cilastatin and Relebactam
After receipt of imipenem-cilastatin-relebactam, ten blood samples will be collected to determine the pharmacokinetics of imipenem and relebactam.
Sponsors
Merck Sharp & Dohme LLC
Joseph L. Kuti, PharmD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Imipenem Clearance | 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). | The clearance in liters/hour of imipenem from the plasma of critically ill patients receiving ECMO. |
| Relebactam Clearance | 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). | The clearance in liters/hour of relebactam from the plasma of critically ill patients receiving ECMO. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Imipenem Area Under the Curve (AUC) | 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). | The AUC in milligram\*hour/liter of imipenem calculated from concentrations collected between zero and 6 hours at steady-state |
| Relebactam Area Under the Curve (AUC) | 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). | The AUC in milligram\*hour/liter of relebactam calculated from concentrations collected between zero and 6 hours at steady-state |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Imipenem, Cilastatin and Relebactam: After receipt of imipenem-cilastatin-relebactam, ten blood samples will be collected to determine the pharmacokinetics of imipenem and relebactam. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Imipenem-Cilastatin-Relebactam |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 50 Years STANDARD_DEVIATION 16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 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 | 2 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 3 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Imipenem Clearance
The clearance in liters/hour of imipenem from the plasma of critically ill patients receiving ECMO.
Time frame: 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Cilastatin-Relebactam | Imipenem Clearance | 15.21 Liters per hour | Standard Deviation 6.52 |
Primary
Relebactam Clearance
The clearance in liters/hour of relebactam from the plasma of critically ill patients receiving ECMO.
Time frame: 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Cilastatin-Relebactam | Relebactam Clearance | 6.95 Liters per hour | Standard Deviation 1.34 |
Secondary
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
Time frame: 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Cilastatin-Relebactam | Imipenem Area Under the Curve (AUC) | 36.9 mg*h/L | Standard Deviation 13.3 |
Secondary
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
Time frame: 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imipenem-Cilastatin-Relebactam | Relebactam Area Under the Curve (AUC) | 45.3 mg*h/L | Standard Deviation 33.2 |