Clinical trial NCT04493151: Imipenem/Cilastatin/Relebactam PK in ECMO
Official title: Pharmacokinetics of Imipenem/Cilastatin/Relebactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)
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: 2020-07-30
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

Eligibility criteria: 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.

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