Suspected or Documented Gram-negative Bacterial Infection
Conditions
Brief summary
This study aims to obtain plasma pharmacokinetic (PK) data and characterize the PK profile of imipenem (IMI), cilastatin (CIL), and relebactam (REL) following administration of a single intravenous (IV) dose of MK-7655A (a fixed ratio combination of imipenem/cilastatin/relebactam), hereafter referred to as IMI/REL.
Interventions
DRUGIMI/REL FDC
IMI/REL is supplied as a single fixed dose combination (FDC) vial; which is administered at a maximum dose of 15 mg/kg IMI and 15 mg/kg CIL (up to 500 mg IMI and 500 mg CIL) and 7.5 mg/kg REL (up to 250 mg REL).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Days to 17 Years
Healthy volunteers
No
Inclusion criteria
* Has a parent or legally acceptable representative (LAR) who provides written informed consent for the trial on the participant's behalf. * Aged from birth to \<18 years old. * Is hospitalized, currently receiving antibacterial treatment for confirmed or suspected Gram-negative bacterial infection, and expected to require hospitalization until at least 24 hours after completion of study drug administration. * Is not of reproductive potential; but if of reproductive potential, agrees to avoid becoming pregnant or impregnating a partner from the time of consent through 24 hours after completion of study drug administration. * Has clinically stable renal function at the time of screening that is judged to be within acceptable ranges. * Has sufficient intravascular access to receive study drug through an existing peripheral or central line.
Exclusion criteria
* Has a personal history of hypersensitivity to imipenem/cilastatin (IMI) or to any of the following: any carbapenem, cephalosporin, penicillin, or other β-lactam agent; or other β-lactamase inhibitors (BLIs) e.g. tazobactam, sulbactam, clavulanic acid, avibactam. * Female is currently pregnant or breast feeding or has a positive serum β-human chorionic gonadotropin (β-hCG) pregnancy test. * Has a history of a seizure disorder requiring ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years. * Has used or plans to use valproic acid or divalproex sodium within 2 weeks prior to screening or at any point between screening and 24 hours after the completion of study drug infusion. * Has received treatment or plans to receive treatment with any carbapenem antibiotic within 48 hours prior to initiation of study drug infusion or at any point between administration of study drug and the last PK sample collection. * Has used or plans to use any of the following medications, which are organic anion transporter (OAT) 1 or OAT3 inhibitors, within 1 week prior to screening or at any point between screening and the last PK sample collection: cimetidine, probenecid, indomethacin, mefenamic acid, furosemide or other loop diuretics (eg, bumetanide, torsemide, ethacrynic acid), angiotensin receptor blockers (eg, valsartan), and ketorolac. * Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days prior to screening. * Has enrolled previously in the current trial and been discontinued, or has received REL for any other reason. * Has a current diagnosis of cystic fibrosis, meningitis, or severe sepsis. * Is expected to survive less than 72 hours after completion of study drug administration. * Has a history of clinically significant renal, hepatic, or hemodynamic instability. * Plans to use cardiopulmonary bypass, extracorporeal membrane oxygenation, hemodialysis, or peritoneal dialysis during the study. * For participants that are 2 to 17 years of age only: weighs outside of the 5th to 95th percentile based on age. * Is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence. * Has a planned blood transfusion within 24 hours of study drug administration or expected before the end of the PK sampling. * Has had significant blood loss (≥5% of total blood volume) within 4 weeks before the screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CIL Volume of Distribution (Vss) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5 | Volume of distribution (Vss) of plasma CIL was not calculated. |
| CIL Terminal Half-Life (t1/2) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Terminal half-life (t1/2) of plasma CIL was not calculated. |
| CIL Clearance (CL) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Systemic clearance (CL) of plasma CIL was not calculated. |
| IMI Central Volume of Distribution (Vc) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Central volume of distribution (Vc) of plasma IMI was calculated. |
| IMI Clearance (CL) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Systemic clearance (CL) of plasma IMI was calculated. |
| Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma imipenem (IMI) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. |
| IMI Maximum Concentration (Cmax) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Maximum plasma concentration (Cmax) of IMI was calculated. Cmax is the peak plasma concentration of study drug after administration. |
| IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Percentage of time spent above the minimum inhibitory concentration (%TMIC) of plasma IMI was calculated. %TMIC is defined as the percentage of time (in hours) in which the lowest concentration of a study drug, completely inhibits growth of the specific organism being tested. |
| Relebactam (REL) AUC0-∞ | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma relebactam (REL) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. |
| REL Maximum Concentration (Cmax) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Maximum plasma concentration (Cmax) of REL was calculated. Cmax is the peak plasma concentration of study drug after administration. |
| REL Clearance (CL) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Systemic clearance (CL) of plasma REL was calculated. |
| REL Central Volume of Distribution (Vc) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Central volume of distribution (Vc) of plasma REL was calculated. |
| Cilastatin (CIL) AUC0-∞ | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma cilastatin (CIL) was not calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. |
| CIL Time to Maximum Concentration (Tmax) | 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5 | Time to maximum plasma concentration (Tmax) of CIL was determined. Tmax is defined as the time after drug administration at which peak drug concentration in plasma occurs. |
| CIL Concentration at End of Infusion (Ceoi) | 30 min after the start of infusion for Cohort 1; 60 min after the start of infusion for Cohorts 2-5 | Concentration at end of infusion (Ceoi) of plasma CIL was determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued Study Drug Due to an AE | Day 1 | Number of participants who discontinued study drug due to an AE was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to 17 days | Number of participants with one or more AEs was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug. |
Countries
Bulgaria, Colombia, Greece, Norway, Poland, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Note: Participant information is shown by age cohort and drug dosage to provide clinically-similar groups for analysis of participant baseline characteristics and safety data. Participant information in pharmacokinetic (PK) outcome measures is shown by age cohort, drug dose received and infusion time in order to provide appropriate and clinically discrete groups for PK analysis and modeling.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: IMI/REL 15/7.5 mg/kg Adolescents (age 12 to \<18 years) administered with a single intravenous (IV) 30-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose of 500/250 mg | 7 |
| Cohort 2: IMI/REL 15/7.5 mg/kg Older children (6 to \<12 years) administered with a single IV 30-minute or 60-minute infusion dose of IMI/REL at 15/7.5 mg/kg, up to a maximum dose of 500/250 mg | 6 |
| Cohort 3: IMI/REL 15/7.5 mg/kg Younger children (2 to \<6 years) administered with a single IV 30-minute or 60-minute infusion dose of IMI/REL at 15/7.5 mg/kg | 6 |
| Cohort 4: IMI/REL 10/5 mg/kg Infants (3 months to \<1 year) administered with a single IV 60-minute infusion dose of IMI/REL at 10/5 mg/kg | 4 |
| Cohort 4: IMI/REL 15/7.5 mg/kg Toddlers (1 to \<2 years) administered with a single IV 60-minute infusion dose of IMI/REL at 15/7.5 mg/kg | 4 |
| Cohort 5: Subcohort 1: IMI/REL 10/5 mg/kg Young infants (4 weeks to \<3 months of age) administered with a single IV 60-minute dose of IMI/REL at 10/5 mg/kg | 6 |
| Cohort 5: Subcohort 2: IMI/REL 10/5 mg/kg Older neonates (1 to \<4 weeks of age) administered with a single IV 60-minute infusion dose of IMI/REL at 10/5 mg/kg | 3 |
| Cohort 5: Subcohort 3: IMI/REL 10/5 mg/kg Younger neonates (\<1 week of age) administered with a single IV 60-minute infusion dose of IMI/REL at 10/5 mg/kg | 2 |
| Cohort 5: Subcohort 1: IMI/REL 15/7.5 mg/kg Young infants (4 weeks to \<3 months of age) administered with a single IV 60-minute infusion dose of IMI/REL at 15/7.5 mg/kg | 2 |
| Cohort 5: Subcohort 2: IMI/REL 15/7.5 mg/kg Older neonates (1 to \<4 weeks of age) administered with a single IV 60-minute infusion dose of IMI/REL at 15/7.5 mg/kg | 3 |
| Cohort 5: Subcohort 3: IMI/REL 15/7.5 mg/kg Younger neonates (\<1 week of age) administered with a single IV 60-minute infusion dose of IMI/REL at 15/7.5 mg/kg | 4 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: IMI/REL 15/7.5 mg/kg | Cohort 2: IMI/REL 15/7.5 mg/kg | Cohort 3: IMI/REL 15/7.5 mg/kg | Cohort 4: IMI/REL 10/5 mg/kg | Cohort 4: IMI/REL 15/7.5 mg/kg | Cohort 5: Subcohort 1: IMI/REL 10/5 mg/kg | Cohort 5: Subcohort 2: IMI/REL 10/5 mg/kg | Cohort 5: Subcohort 3: IMI/REL 10/5 mg/kg | Cohort 5: Subcohort 1: IMI/REL 15/7.5 mg/kg | Cohort 5: Subcohort 2: IMI/REL 15/7.5 mg/kg | Cohort 5: Subcohort 3: IMI/REL 15/7.5 mg/kg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants |
| Age, Customized Adults (18-64 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 6 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 12 Participants |
| Age, Customized From 65-84 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants | 6 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 16 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 3 Participants | 4 Participants | 12 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 6 Participants | 4 Participants | 3 Participants | 2 Participants | 5 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 7 Participants | 6 Participants | 4 Participants | 3 Participants | 2 Participants | 5 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 37 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 4 Participants | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 28 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 4 | 0 / 5 | 0 / 3 | 0 / 2 | 0 / 2 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 1 / 7 | 0 / 6 | 3 / 6 | 1 / 4 | 2 / 4 | 1 / 5 | 0 / 3 | 0 / 2 | 0 / 2 | 0 / 3 | 0 / 4 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 4 | 0 / 5 | 0 / 3 | 0 / 2 | 0 / 2 | 0 / 3 | 0 / 4 |
Outcome results
Primary
Cilastatin (CIL) AUC0-∞
Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma cilastatin (CIL) was not calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: Due to sparse PK sampling schedule, per participant data could not be calculated.
Primary
CIL Clearance (CL)
Systemic clearance (CL) of plasma CIL was not calculated.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: Due to sparse PK sampling schedule, per participant data could not be calculated.
Primary
CIL Concentration at End of Infusion (Ceoi)
Concentration at end of infusion (Ceoi) of plasma CIL was determined.
Time frame: 30 min after the start of infusion for Cohort 1; 60 min after the start of infusion for Cohorts 2-5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for CIL Ceoi
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 86.9 μM | Geometric Coefficient of Variation 41 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 122 μM | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 111 μM | Geometric Coefficient of Variation 51 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 80.5 μM | Geometric Coefficient of Variation 22 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 74.8 μM | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 102 μM | Geometric Coefficient of Variation 32 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 80.9 μM | Geometric Coefficient of Variation 62 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 37.0 μM | Geometric Coefficient of Variation 64 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 94.5 μM | Geometric Coefficient of Variation 42 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 63.6 μM | Geometric Coefficient of Variation 28 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | CIL Concentration at End of Infusion (Ceoi) | 107.0 μM | Geometric Coefficient of Variation 20 |
Primary
CIL Terminal Half-Life (t1/2)
Terminal half-life (t1/2) of plasma CIL was not calculated.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: Due to sparse PK sampling schedule, per participant data could not be calculated.
Primary
CIL Time to Maximum Concentration (Tmax)
Time to maximum plasma concentration (Tmax) of CIL was determined. Tmax is defined as the time after drug administration at which peak drug concentration in plasma occurs.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for CIL Tmax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 0.58 Hours |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 0.53 Hours |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 1.1 Hours |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 0.58 Hours |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 1.1 Hours |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 0.58 Hours |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 1.1 Hours |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 1.1 Hours |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 1.2 Hours |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 1.1 Hours |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | CIL Time to Maximum Concentration (Tmax) | 1.2 Hours |
Primary
CIL Volume of Distribution (Vss)
Volume of distribution (Vss) of plasma CIL was not calculated.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
Population: Due to sparse PK sampling schedule, per participant data could not be calculated.
Primary
IMI Central Volume of Distribution (Vc)
Central volume of distribution (Vc) of plasma IMI was calculated.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for IMI Vc
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | IMI Central Volume of Distribution (Vc) | 10.27 Liters | Geometric Coefficient of Variation 16.2 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Central Volume of Distribution (Vc) | 8.00 Liters | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | IMI Central Volume of Distribution (Vc) | 4.33 Liters | Geometric Coefficient of Variation 5.2 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | IMI Central Volume of Distribution (Vc) | 9.60 Liters | Geometric Coefficient of Variation 2.4 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | IMI Central Volume of Distribution (Vc) | 8.70 Liters | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Central Volume of Distribution (Vc) | 3.49 Liters | Geometric Coefficient of Variation 19.6 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Central Volume of Distribution (Vc) | 2.49 Liters | Geometric Coefficient of Variation 34.6 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Central Volume of Distribution (Vc) | 2.39 Liters | Geometric Coefficient of Variation 53.2 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Central Volume of Distribution (Vc) | 1.52 Liters | Geometric Coefficient of Variation 35 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Central Volume of Distribution (Vc) | 1.06 Liters | Geometric Coefficient of Variation 29.6 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Central Volume of Distribution (Vc) | 0.95 Liters | Geometric Coefficient of Variation 34.2 |
Primary
IMI Clearance (CL)
Systemic clearance (CL) of plasma IMI was calculated.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for IMI CL
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | IMI Clearance (CL) | 12.58 L/hr | Geometric Coefficient of Variation 18.4 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Clearance (CL) | 9.60 L/hr | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | IMI Clearance (CL) | 5.25 L/hr | Geometric Coefficient of Variation 9.2 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | IMI Clearance (CL) | 11.67 L/hr | Geometric Coefficient of Variation 27.6 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | IMI Clearance (CL) | 11.74 L/hr | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Clearance (CL) | 5.31 L/hr | Geometric Coefficient of Variation 29.7 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Clearance (CL) | 4.43 L/hr | Geometric Coefficient of Variation 45.2 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Clearance (CL) | 3.31 L/hr | Geometric Coefficient of Variation 60.1 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Clearance (CL) | 1.70 L/hr | Geometric Coefficient of Variation 48.1 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Clearance (CL) | 1.10 L/hr | Geometric Coefficient of Variation 26.2 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Clearance (CL) | 0.66 L/hr | Geometric Coefficient of Variation 20.4 |
Primary
IMI Maximum Concentration (Cmax)
Maximum plasma concentration (Cmax) of IMI was calculated. Cmax is the peak plasma concentration of study drug after administration.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose pharmacokinetic (PK) data point available for IMI Cmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | IMI Maximum Concentration (Cmax) | 107.6 μM | Geometric Coefficient of Variation 16.4 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Maximum Concentration (Cmax) | 126.0 μM | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | IMI Maximum Concentration (Cmax) | 123.0 μM | Geometric Coefficient of Variation 20.6 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | IMI Maximum Concentration (Cmax) | 114.2 μM | Geometric Coefficient of Variation 9.2 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | IMI Maximum Concentration (Cmax) | 110.6 μM | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Maximum Concentration (Cmax) | 150.3 μM | Geometric Coefficient of Variation 6.7 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Maximum Concentration (Cmax) | 125.1 μM | Geometric Coefficient of Variation 25.2 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Maximum Concentration (Cmax) | 64.9 μM | Geometric Coefficient of Variation 29.6 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Maximum Concentration (Cmax) | 127.7 μM | Geometric Coefficient of Variation 36 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Maximum Concentration (Cmax) | 79.4 μM | Geometric Coefficient of Variation 26.4 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Maximum Concentration (Cmax) | 119.8 μM | Geometric Coefficient of Variation 16.8 |
Primary
Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞)
Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma imipenem (IMI) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose pharmacokinetic (PK) data point available for IMI AUC0-∞
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 134.7 μM*hr | Geometric Coefficient of Variation 19.8 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 153.2 μM*hr | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 219.4 μM*hr | Geometric Coefficient of Variation 39.2 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 139.4 μM*hr | Geometric Coefficient of Variation 26.6 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 140 μM*hr | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 156 μM*hr | Geometric Coefficient of Variation 18.9 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 163 μM*hr | Geometric Coefficient of Variation 31.2 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 95.4 μM*hr | Geometric Coefficient of Variation 39.3 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 219.2 μM*hr | Geometric Coefficient of Variation 39.6 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 152.5 μM*hr | Geometric Coefficient of Variation 14.1 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞) | 271.3 μM*hr | Geometric Coefficient of Variation 15.4 |
Primary
IMI Percentage of Time Above the Minimum Concentration (%TMIC)
Percentage of time spent above the minimum inhibitory concentration (%TMIC) of plasma IMI was calculated. %TMIC is defined as the percentage of time (in hours) in which the lowest concentration of a study drug, completely inhibits growth of the specific organism being tested.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for IMI %TMIC
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 56.5 Percentage of time | Geometric Coefficient of Variation 17.1 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 58.3 Percentage of time | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 80.3 Percentage of time | Geometric Coefficient of Variation 26.7 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 61.6 Percentage of time | Geometric Coefficient of Variation 25.1 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 56.7 Percentage of time | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 50.1 Percentage of time | Geometric Coefficient of Variation 15.7 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 57.7 Percentage of time | Geometric Coefficient of Variation 18.8 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 50.4 Percentage of time | Geometric Coefficient of Variation 30.5 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 73.9 Percentage of time | Geometric Coefficient of Variation 19.7 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 70.2 Percentage of time | Geometric Coefficient of Variation 10.6 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | IMI Percentage of Time Above the Minimum Concentration (%TMIC) | 93.7 Percentage of time | Geometric Coefficient of Variation 9.3 |
Primary
REL Central Volume of Distribution (Vc)
Central volume of distribution (Vc) of plasma REL was calculated.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for REL Vc
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | REL Central Volume of Distribution (Vc) | 10.58 Liters | Geometric Coefficient of Variation 17.2 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | REL Central Volume of Distribution (Vc) | 6.76 Liters | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | REL Central Volume of Distribution (Vc) | 4.95 Liters | Geometric Coefficient of Variation 1.6 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | REL Central Volume of Distribution (Vc) | 9.81 Liters | Geometric Coefficient of Variation 6.1 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | REL Central Volume of Distribution (Vc) | 9.38 Liters | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | REL Central Volume of Distribution (Vc) | 3.83 Liters | Geometric Coefficient of Variation 13.8 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Central Volume of Distribution (Vc) | 2.88 Liters | Geometric Coefficient of Variation 27.4 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | REL Central Volume of Distribution (Vc) | 2.43 Liters | Geometric Coefficient of Variation 38.8 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Central Volume of Distribution (Vc) | 1.70 Liters | Geometric Coefficient of Variation 21.1 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | REL Central Volume of Distribution (Vc) | 1.21 Liters | Geometric Coefficient of Variation 24.6 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Central Volume of Distribution (Vc) | 0.90 Liters | Geometric Coefficient of Variation 36.7 |
Primary
REL Clearance (CL)
Systemic clearance (CL) of plasma REL was calculated.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for REL CL
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | REL Clearance (CL) | 8.98 L/hr | Geometric Coefficient of Variation 20.7 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | REL Clearance (CL) | 6.10 L/hr | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | REL Clearance (CL) | 3.96 L/hr | Geometric Coefficient of Variation 28.9 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | REL Clearance (CL) | 8.03 L/hr | Geometric Coefficient of Variation 35.7 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | REL Clearance (CL) | 8.65 L/hr | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | REL Clearance (CL) | 4.20 L/hr | Geometric Coefficient of Variation 40.8 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Clearance (CL) | 3.65 L/hr | Geometric Coefficient of Variation 54.1 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | REL Clearance (CL) | 2.56 L/hr | Geometric Coefficient of Variation 54.5 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Clearance (CL) | 1.27 L/hr | Geometric Coefficient of Variation 62.9 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | REL Clearance (CL) | 0.74 L/hr | Geometric Coefficient of Variation 27 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Clearance (CL) | 0.35 L/hr | Geometric Coefficient of Variation 30.7 |
Primary
Relebactam (REL) AUC0-∞
Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma relebactam (REL) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for REL AUC0-∞
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | Relebactam (REL) AUC0-∞ | 80.1 μM*hr | Geometric Coefficient of Variation 20 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Relebactam (REL) AUC0-∞ | 105.6 μM*hr | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | Relebactam (REL) AUC0-∞ | 123.8 μM*hr | Geometric Coefficient of Variation 59.5 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | Relebactam (REL) AUC0-∞ | 90.3 μM*hr | Geometric Coefficient of Variation 35.1 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | Relebactam (REL) AUC0-∞ | 80.2 μM*hr | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Relebactam (REL) AUC0-∞ | 85.7 μM*hr | Geometric Coefficient of Variation 32.4 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Relebactam (REL) AUC0-∞ | 81.7 μM*hr | Geometric Coefficient of Variation 42 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | Relebactam (REL) AUC0-∞ | 52.8 μM*hr | Geometric Coefficient of Variation 33.6 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Relebactam (REL) AUC0-∞ | 126.6 μM*hr | Geometric Coefficient of Variation 53.7 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | Relebactam (REL) AUC0-∞ | 91.8 μM*hr | Geometric Coefficient of Variation 18.3 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Relebactam (REL) AUC0-∞ | 220.7 μM*hr | Geometric Coefficient of Variation 34.1 |
Primary
REL Maximum Concentration (Cmax)
Maximum plasma concentration (Cmax) of REL was calculated. Cmax is the peak plasma concentration of study drug after administration.
Time frame: 30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Population: All allocated participants who were compliant with the protocol and had at least 1 post-dose PK data point available for REL Cmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | REL Maximum Concentration (Cmax) | 49.33 μM | Geometric Coefficient of Variation 23 |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | REL Maximum Concentration (Cmax) | 86.52 μM | — |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | REL Maximum Concentration (Cmax) | 60.32 μM | Geometric Coefficient of Variation 30.7 |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | REL Maximum Concentration (Cmax) | 57.44 μM | Geometric Coefficient of Variation 26.1 |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | REL Maximum Concentration (Cmax) | 48.73 μM | — |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | REL Maximum Concentration (Cmax) | 59.05 μM | Geometric Coefficient of Variation 9.08 |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Maximum Concentration (Cmax) | 48.59 μM | Geometric Coefficient of Variation 22.9 |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | REL Maximum Concentration (Cmax) | 32.74 μM | Geometric Coefficient of Variation 15 |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Maximum Concentration (Cmax) | 59.55 μM | Geometric Coefficient of Variation 17.1 |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | REL Maximum Concentration (Cmax) | 34.22 μM | Geometric Coefficient of Variation 17.3 |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | REL Maximum Concentration (Cmax) | 61.04 μM | Geometric Coefficient of Variation 21.9 |
Secondary
Number of Participants Who Discontinued Study Drug Due to an AE
Number of participants who discontinued study drug due to an AE was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug.
Time frame: Day 1
Population: All allocated participants who received infusion (including partial doses) of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
Number of participants with one or more AEs was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug.
Time frame: Up to 17 days
Population: All allocated participants who received infusion (including partial doses) of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: IMI/REL 500/250 mg 30-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 1 Participants |
| Cohort 2: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Cohort 2: IMI/REL 15/7.5 mg/kg mg 60-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| Cohort 2: IMI/REL 500/250 mg 30-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 1 Participants |
| Cohort 2: IMI/REL 500/250 mg 60-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 2 Participants |
| Cohort 3: IMI/REL 15/7.5 mg/kg 30-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 1 Participants |
| Cohort 3: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Cohort 4: IMI/REL 10/5 mg/kg 60-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Cohort 4: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Cohort 5: IMI/REL 10/5 mg/kg 60-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Cohort 5: IMI/REL 15/7.5 mg/kg 60-minute Infusion | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |