Bacterial Infections, Complicated Infection
Conditions
Keywords
Phase I, Safety, tolerability, healthy.
Brief summary
This is a randomised, double-blind, 3-part study designed to investigate the safety and tolerability of ATM-AVI. The study aims to characterise the pharmacokinetics of ATM-AVI, when both drugs are administered alone (ATM or AVI) and in combination (ATM-AVI), following single administration, and following multiple administrations of ATM-AVI in healthy male and female (females of nonchildbearing potential) volunteers both young and elderly.
Detailed description
A Phase I, Randomised, Double-blind, 3-Part Study in Healthy Young and Elderly Subjects to Assess the Safety and Tolerability, and Investigate the Pharmacokinetics of Aztreonam and Avibactam given Alone and in Combination (ATM-AVI)
Interventions
DRUGcombination of Aztreonam - Avibactam (ATM-AVI)
PART A: ATM-AVI IV infusion. PART B and C: ATM-AVI IV infusions.
DRUGAvibactam (AVI)
PART A: AVI IV infusion
DRUGAztreonam (ATM)
PART A: ATM IV infusion
DRUGPlacebo
PART A, PART B, PART C: matching placebo IV infusions
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
Yes
Inclusion criteria
* Provision of signed and dated, written informed consent prior to any study specific procedures * Healthy young male and female volunteers aged 18 to 45 years (inclusive) and healthy elderly volunteers aged 65 or older (Part C) with suitable veins for cannulation or repeated venipuncture * Have a body mass index (BMI) between 19 and 30 kg/m2 * Be able to understand and willing to comply with study procedures, restrictions, and requirements, as judged by the PI
Exclusion criteria
* History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study * History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs * Known history of severe allergy to betalactam and/or L-arginine * History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to ATM or AVI * Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks prior to the first administration of IP
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Profile - Number of Subjects With at Least 1 AE | Informed consent (up to 28 days before first dose) to follow up period (max of 22 days after first dose for Part A, a max of 28 days after first dose in Part B, max 17 days in Part C) | from screening visit (Day -28) to 3 to 7 days post treatment period 3 (up to Day 22) in Part A, 3 to 7 days after receiving the final dose on Day 11 (days 14 to 18) in Part B, and 3 to 7 days after receiving the final dose on Day 10 (days 13 to 17) in Part C. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | Terminal half-life (t1/2), on Day 1 after single infusion and at steady state after multiple infusion. |
| PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | Day 1 | Time to Cmax (tmax) |
| PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | Area under the plasma concentration-time curve from zero extrapolated to infinity (AUC µg\*h/mL) or AUC(0-last) in Part A on Day 1 after single infusion, area under the plasma concentration-time curve at steady state after multiple infusion (AUCss µg\*h/mL). |
| PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | Systemic clearence (CL) and renal clearance (CLr) on Day 1 after single infusion and at steady state after multiple infusion. |
| PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | Volume of distribution at steady state (Vss). |
| PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | Maximum plasma concentration (Cmax µg/mL) on Day 1 after single infusion , maximum plasma concentration at steady state (Css,max µg/mL) after multiple infusion. |
Countries
United Kingdom
Participant flow
Recruitment details
First subject enrolled 27 September 2012 and last subject last visit was 30 December 2014. Subjects were healthy male and female volunteers both young and elderly. Healthy volunteers were given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study and could discontinue at any time.
Pre-assignment details
A Screening visit was conducted within 28 days before admission to the study centre. 222 volunteers were screend, 92 volunteers were entered into the study. Healthy volunteers were admitted to the study centre on Day -1 of either Part A, Part B or Part C.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo Placebo | 4 |
| Part A: Drug Aztreonam (ATM) 2000mg, Avibactam (AVI) 600mg, ATM 2000mg +AVI 600mg (crossover) | 8 |
| Part B: Placebo Placebo | 16 |
| Part B: Cohort 1 Drug ATM (2000mg) + AVI (375mg) | 8 |
| Part B: Cohort 2 Drug ATM (2000mg) + AVI (600mg) | 4 |
| Part B: Cohort 3 Drug ATM (1500mg) + AVI (600mg) | 8 |
| Part B: Cohort 4 Drug ATM (1500mg) + AVI (450mg) | 10 |
| Part B: Cohort 5 Drug ATM (1500mg) + AVI (410mg) | 10 |
| Part C: Placebo Placebo | 6 |
| Part C: Cohort 1 Drug Aged 18-45: ATM (500mg followed by 1500mg) + AVI (136.7mg followed by 410mg) | 10 |
| Part C: Cohort 2 Drug Aged \>65: ATM (500mg followed by 1500mg) + AVI (136.7mg + 410mg) | 8 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Placebo | Part A: Drug | Part B: Placebo | Part B: Cohort 1 Drug | Part B: Cohort 2 Drug | Part B: Cohort 3 Drug | Part B: Cohort 4 Drug | Part B: Cohort 5 Drug | Part C: Placebo | Part C: Cohort 1 Drug | Part C: Cohort 2 Drug | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 33.8 years STANDARD_DEVIATION 6.9 | 31.3 years STANDARD_DEVIATION 7.1 | 27.4 years STANDARD_DEVIATION 5 | 30.3 years STANDARD_DEVIATION 4.9 | 27.8 years STANDARD_DEVIATION 1.9 | 29.4 years STANDARD_DEVIATION 9.9 | 29.7 years STANDARD_DEVIATION 7.3 | 30.6 years STANDARD_DEVIATION 6.3 | 51.3 years STANDARD_DEVIATION 19.4 | 32.9 years STANDARD_DEVIATION 8.4 | 68.5 years STANDARD_DEVIATION 2.9 | 34.8 years STANDARD_DEVIATION 14 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 16 Participants | 8 Participants | 4 Participants | 8 Participants | 10 Participants | 10 Participants | 5 Participants | 10 Participants | 6 Participants | 89 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 | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 4 | 2 / 8 | 3 / 16 | 4 / 8 | 2 / 4 | 6 / 8 | 8 / 10 | 3 / 10 | 3 / 6 | 5 / 10 | 7 / 8 | 0 / 7 | 2 / 8 | 0 / 7 |
| serious Total, serious adverse events | 0 / 4 | 0 / 8 | 0 / 16 | 0 / 8 | 0 / 4 | 0 / 8 | 0 / 10 | 0 / 10 | 1 / 6 | 0 / 10 | 0 / 8 | 0 / 7 | 0 / 8 | 0 / 7 |
Outcome results
Primary
Safety Profile - Number of Subjects With at Least 1 AE
from screening visit (Day -28) to 3 to 7 days post treatment period 3 (up to Day 22) in Part A, 3 to 7 days after receiving the final dose on Day 11 (days 14 to 18) in Part B, and 3 to 7 days after receiving the final dose on Day 10 (days 13 to 17) in Part C.
Time frame: Informed consent (up to 28 days before first dose) to follow up period (max of 22 days after first dose for Part A, a max of 28 days after first dose in Part B, max 17 days in Part C)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part A: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 1 Participants |
| Part A: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part A: Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 1 Participants |
| Part A: Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part A: Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 2 Participants |
| Part B: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part B: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 3 Participants |
| Part B: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part B: Cohort 1 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part B: Cohort 1 Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part B: Cohort 1 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 4 Participants |
| Part B: Cohort 2 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 2 Participants |
| Part B: Cohort 2 Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 2 Participants |
| Part B: Cohort 2 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part B: Cohort 3 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part B: Cohort 3 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 6 Participants |
| Part B: Cohort 3 Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 1 Participants |
| Part B: Cohort 4 Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part B: Cohort 4 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 8 Participants |
| Part B: Cohort 4 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part B: Cohort 5 Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part B: Cohort 5 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 3 Participants |
| Part B: Cohort 5 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part C: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 1 Participants |
| Part C: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 3 Participants |
| Part C: Placebo | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part C: Cohort 1 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 5 Participants |
| Part C: Cohort 1 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part C: Cohort 1 Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part C: Cohort 2 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 7 Participants |
| Part C: Cohort 2 Drug | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part C: Cohort 2 Drug | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part A: Aztreonam (ATM) 2000mg | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 0 Participants |
| Part A: Aztreonam (ATM) 2000mg | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part A: Aztreonam (ATM) 2000mg | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part A: Avibactam (AVI) 600mg | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
| Part A: Avibactam (AVI) 600mg | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 1 Participants |
| Part A: Avibactam (AVI) 600mg | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 2 Participants |
| Part A: ATM 2000mg + AVI 600mg | Safety Profile - Number of Subjects With at Least 1 AE | At least 1 AE leading to discontinuation | 0 Participants |
| Part A: ATM 2000mg + AVI 600mg | Safety Profile - Number of Subjects With at Least 1 AE | Number of subjects with at least 1 AE | 0 Participants |
| Part A: ATM 2000mg + AVI 600mg | Safety Profile - Number of Subjects With at Least 1 AE | Subjects with at least 1 AE with outcome of death | 0 Participants |
Secondary
PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C
Area under the plasma concentration-time curve from zero extrapolated to infinity (AUC µg\*h/mL) or AUC(0-last) in Part A on Day 1 after single infusion, area under the plasma concentration-time curve at steady state after multiple infusion (AUCss µg\*h/mL).
Time frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C
Population: Pharmacokinetic analysis set. Please note, PK parameters have not been calculated where data is available in \<3 subjects as this is considered to lack robustness.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | NA ug*h/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | NA ug*h/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | NA ug*h/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | NA ug*h/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 375 ug*h/mL | Geometric Coefficient of Variation 12.8 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | NA ug*h/mL | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | 52.6 ug*h/mL | Geometric Coefficient of Variation 22.5 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 58.3 ug*h/mL | Geometric Coefficient of Variation 17.7 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | 372 ug*h/mL | Geometric Coefficient of Variation 15.2 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | NA ug*h/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | NA ug*h/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | NA ug*h/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | NA ug*h/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | NA ug*h/mL | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | 26.1 ug*h/mL | Geometric Coefficient of Variation 13 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 31.8 ug*h/mL | Geometric Coefficient of Variation 12.5 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | 275 ug*h/mL | Geometric Coefficient of Variation 14 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 345 ug*h/mL | Geometric Coefficient of Variation 16.3 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 326 ug*h/mL | Geometric Coefficient of Variation 5.5 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | NA ug*h/mL | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 47.8 ug*h/mL | Geometric Coefficient of Variation 12.5 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | NA ug*h/mL | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | 231 ug*h/mL | Geometric Coefficient of Variation 15.9 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | 43.3 ug*h/mL | Geometric Coefficient of Variation 11.7 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 283 ug*h/mL | Geometric Coefficient of Variation 17.7 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 53.1 ug*h/mL | Geometric Coefficient of Variation 12.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | 223 ug*h/mL | Geometric Coefficient of Variation 7.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 35.7 ug*h/mL | Geometric Coefficient of Variation 11.8 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | 29.0 ug*h/mL | Geometric Coefficient of Variation 10.2 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 270 ug*h/mL | Geometric Coefficient of Variation 9.8 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | 203 ug*h/mL | Geometric Coefficient of Variation 11.1 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 31.4 ug*h/mL | Geometric Coefficient of Variation 14.7 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 250 ug*h/mL | Geometric Coefficient of Variation 13.3 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | 26.7 ug*h/mL | Geometric Coefficient of Variation 12.6 |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | NA ug*h/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | NA ug*h/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | NA ug*h/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | NA ug*h/mL | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | 29.3 ug*h/mL | Geometric Coefficient of Variation 19.6 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 41.9 ug*h/mL | Geometric Coefficient of Variation 17.1 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 276 ug*h/mL | Geometric Coefficient of Variation 13.5 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | 211 ug*h/mL | Geometric Coefficient of Variation 15.7 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - AVI in combination (Day 1) | 52.3 ug*h/mL | Geometric Coefficient of Variation 11 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - AVI in combination | 38.8 ug*h/mL | Geometric Coefficient of Variation 14 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Avibactam (AVI)alone | NA ug*h/mL | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUCss (ug*h/mL) - ATM in combination | 259 ug*h/mL | Geometric Coefficient of Variation 12.1 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - Aztreonam (ATM) alone | NA ug*h/mL | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | AUC (ug*h/mL) - ATM in combination (Day 1) | 308 ug*h/mL | Geometric Coefficient of Variation 12 |
Secondary
PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C
Maximum plasma concentration (Cmax µg/mL) on Day 1 after single infusion , maximum plasma concentration at steady state (Css,max µg/mL) after multiple infusion.
Time frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C
Population: Pharmacokinetic analysis set. Please note, PK parameters have not been calculated where data is available in \<3 subjects as this is considered to lack robustness. Placebo arms are not evaluated. Values shown where analysed (eg. not applicable for ATM alone in combination cohorts)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | NA ug/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | NA ug/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | NA ug/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | NA ug/mL | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | NA ug/mL | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | 26.8 ug/mL | Geometric Coefficient of Variation 14.2 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 137 ug/mL | Geometric Coefficient of Variation 11.3 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 137 ug/mL | Geometric Coefficient of Variation 11.3 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | NA ug/mL | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | 143 ug/mL | Geometric Coefficient of Variation 14 |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | NA ug/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | NA ug/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | NA ug/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | NA ug/mL | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | 14.5 ug/mL | Geometric Coefficient of Variation 15.9 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 16.0 ug/mL | Geometric Coefficient of Variation 10.1 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | 124 ug/mL | Geometric Coefficient of Variation 9 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 123 ug/mL | Geometric Coefficient of Variation 16.7 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 25.1 ug/mL | Geometric Coefficient of Variation 5.8 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 123 ug/mL | Geometric Coefficient of Variation 6.2 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | NA ug/mL | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | NA ug/mL | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 82.4 ug/mL | Geometric Coefficient of Variation 16 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | 80.9 ug/mL | Geometric Coefficient of Variation 12.9 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 19.3 ug/mL | Geometric Coefficient of Variation 16.4 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | 17.6 ug/mL | Geometric Coefficient of Variation 12.2 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 63.2 ug/mL | Geometric Coefficient of Variation 9.4 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | 62.6 ug/mL | Geometric Coefficient of Variation 9.1 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | 8.69 ug/mL | Geometric Coefficient of Variation 9.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 9.99 ug/mL | Geometric Coefficient of Variation 11.2 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | 55.7 ug/mL | Geometric Coefficient of Variation 9 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 8.68 ug/mL | Geometric Coefficient of Variation 14 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 59.2 ug/mL | Geometric Coefficient of Variation 13.1 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | 8.36 ug/mL | Geometric Coefficient of Variation 16.5 |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | NA ug/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | NA ug/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | NA ug/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | NA ug/mL | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | 57.2 ug/mL | Geometric Coefficient of Variation 14.9 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 12.1 ug/mL | Geometric Coefficient of Variation 18.4 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | 8.88 ug/mL | Geometric Coefficient of Variation 19.9 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 75.6 ug/mL | Geometric Coefficient of Variation 13.8 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - ATM in combination | 66.2 ug/mL | Geometric Coefficient of Variation 13.3 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM in combination (Day1) | 81.6 ug/mL | Geometric Coefficient of Variation 11.8 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Css, max (ug/mL) - AVI in combination | 11.6 ug/mL | Geometric Coefficient of Variation 15.1 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - ATM alone | NA ug/mL | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI in combination (Day1) | 15.2 ug/mL | Geometric Coefficient of Variation 13.6 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Cmax (ug/mL) - AVI alone | NA ug/mL | — |
Secondary
PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C
Systemic clearence (CL) and renal clearance (CLr) on Day 1 after single infusion and at steady state after multiple infusion.
Time frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C
Population: Pharmacokinetic analysis set. Please note, PK parameters have not been calculated where data is available in \<3 subjects as this is considered to lack robustness. Placebo arms are not evaluated. Values shown where analysed (eg. not applicable for ATM alone in combination cohorts)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | NA L/h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | 5.37 L/h | Geometric Coefficient of Variation 15.2 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | NA L/h | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | 5.33 L/h | Geometric Coefficient of Variation 12.9 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | 11.4 L/h | Geometric Coefficient of Variation 22.4 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 3.78 L/h | Geometric Coefficient of Variation 17.6 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | NA L/h | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | 10.3 L/h | Geometric Coefficient of Variation 17.7 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | 3.93 L/h | Geometric Coefficient of Variation 19 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 8.71 L/h | Geometric Coefficient of Variation 17.1 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | NA L/h | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | NA L/h | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | 9.77 L/h | Geometric Coefficient of Variation 21.6 |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | NA L/h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | 11.8 L/h | Geometric Coefficient of Variation 12.4 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | 5.79 L/h | Geometric Coefficient of Variation 16.3 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | 12.4 L/h | Geometric Coefficient of Variation 24.8 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | 14.3 L/h | Geometric Coefficient of Variation 13.1 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | 4.66 L/h | Geometric Coefficient of Variation 18.9 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | 7.27 L/h | Geometric Coefficient of Variation 14 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 10.6 L/h | Geometric Coefficient of Variation 19.3 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 4.04 L/h | Geometric Coefficient of Variation 14.4 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 10.9 L/h | Geometric Coefficient of Variation 12.5 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 4.10 L/h | Geometric Coefficient of Variation 7.4 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | 12.5 L/h | Geometric Coefficient of Variation 12.7 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | NA L/h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | 6.15 L/h | Geometric Coefficient of Variation 5.5 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | 5.29 L/h | Geometric Coefficient of Variation 17.8 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 4.18 L/h | Geometric Coefficient of Variation 14 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | 11.3 L/h | Geometric Coefficient of Variation 12.8 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 11.1 L/h | Geometric Coefficient of Variation 11.7 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | 6.49 L/h | Geometric Coefficient of Variation 15.9 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | 4.93 L/h | Geometric Coefficient of Variation 15.2 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | 13.8 L/h | Geometric Coefficient of Variation 11.7 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | 13.9 L/h | Geometric Coefficient of Variation 11.5 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 4.09 L/h | Geometric Coefficient of Variation 21.5 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | 5.56 L/h | Geometric Coefficient of Variation 9.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | 5.07 L/h | Geometric Coefficient of Variation 27.8 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | 12.6 L/h | Geometric Coefficient of Variation 11.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | 15.5 L/h | Geometric Coefficient of Variation 10.4 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | 6.72 L/h | Geometric Coefficient of Variation 7.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 11.9 L/h | Geometric Coefficient of Variation 24.6 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | 14.7 L/h | Geometric Coefficient of Variation 24.6 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | 13.1 L/h | Geometric Coefficient of Variation 14.8 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | 5.25 L/h | Geometric Coefficient of Variation 13.5 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | 5.99 L/h | Geometric Coefficient of Variation 13.4 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | 14.5 L/h | Geometric Coefficient of Variation 14.6 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 12.5 L/h | Geometric Coefficient of Variation 15.6 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | 15.4 L/h | Geometric Coefficient of Variation 12.7 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 4.43 L/h | Geometric Coefficient of Variation 11.8 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | 7.39 L/h | Geometric Coefficient of Variation 11.1 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | NA L/h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | 13.0 L/h | Geometric Coefficient of Variation 22 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 10.8 L/h | Geometric Coefficient of Variation 16.3 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | NA L/h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | 14.0 L/h | Geometric Coefficient of Variation 19.7 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | NA L/h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 4.22 L/h | Geometric Coefficient of Variation 17.2 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | 4.97 L/h | Geometric Coefficient of Variation 19 |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | 7.10 L/h | Geometric Coefficient of Variation 15.8 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Steady state) | 3.99 L/h | Geometric Coefficient of Variation 21 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Steady state) | 5.79 L/h | Geometric Coefficient of Variation 12.2 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI alone | NA L/h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - ATM in combination (Day 1) | NA L/h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Steady state) | 10.6 L/h | Geometric Coefficient of Variation 14 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI alone | NA L/h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Day 1) | 7.78 L/h | Geometric Coefficient of Variation 27.9 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL (L/h) - ATM alone | NA L/h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CL(L/h) - AVI in combination (Day 1) | NA L/h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM in comination (Day 1) | 3.41 L/h | Geometric Coefficient of Variation 16.9 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - AVI in comination (Steady state) | 9.49 L/h | Geometric Coefficient of Variation 18.7 |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | CLr (L/h) - ATM alone | NA L/h | — |
Secondary
PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C
Terminal half-life (t1/2), on Day 1 after single infusion and at steady state after multiple infusion.
Time frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C
Population: Pharmacokinetic analysis set. Please note, PK parameters have not been calculated where data is available in \<3 subjects as this is considered to lack robustness. Placebo arms are not evaluated. Values shown where analysed (eg. not applicable for ATM alone in combination cohorts)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | NA h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | NA h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | 2.22 h | Geometric Coefficient of Variation 26.3 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | 2.09 h | Geometric Coefficient of Variation 14 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | 2.35 h | Geometric Coefficient of Variation 25.4 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | 1.98 h | Geometric Coefficient of Variation 18.9 |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | NA h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | NA h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | 2.24 h | Geometric Coefficient of Variation 16.6 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | 2.17 h | Geometric Coefficient of Variation 30.9 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | 2.82 h | Geometric Coefficient of Variation 41.1 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | 1.98 h | Geometric Coefficient of Variation 3.3 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | 2.61 h | Geometric Coefficient of Variation 10.1 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | 1.90 h | Geometric Coefficient of Variation 16.2 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | 2.14 h | Geometric Coefficient of Variation 21.2 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | 2.26 h | Geometric Coefficient of Variation 30.1 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | 2.28 h | Geometric Coefficient of Variation 25.9 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | 1.85 h | Geometric Coefficient of Variation 27.4 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | NA h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | NA h | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | NA h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | NA h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Avibactam (AVI)alone | NA h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - AVI in combination | NA h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - ATM in combination | NA h | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | t1/2 (h) - Aztreonam (ATM) alone | NA h | — |
Secondary
PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C
Time to Cmax (tmax)
Time frame: Day 1
Population: Pharmacokinetic analysis set. Please note, PK parameters have not been calculated where data is available in \<3 subjects as this is considered to lack robustness. Placebo arms are not evaluated. Values shown where analysed (eg. not applicable for ATM alone in combination cohorts)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | NA (h) |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | NA (h) |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | 0.98 (h) |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 0.98 (h) |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 0.98 (h) |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | 0.98 (h) |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | NA (h) |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | NA (h) |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 0.98 (h) |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 0.98 (h) |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 0.98 (h) |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 0.98 (h) |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 1.98 (h) |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 1.98 (h) |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 2.98 (h) |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 2.98 (h) |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 2.98 (h) |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 2.50 (h) |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | NA (h) |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | NA (h) |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 2.98 (h) |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 2.98 (h) |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI alone | NA (h) |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - AVI in combination (Day 1) | 2.98 (h) |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM in combination (Day 1) | 2.98 (h) |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | tmax (h) - ATM alone | NA (h) |
Secondary
PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C
Volume of distribution at steady state (Vss).
Time frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C
Population: Pharmacokinetic analysis set. Please note, PK parameters have not been calculated where data is available in \<3 subjects as this is considered to lack robustness. Placebo arms are not evaluated. Values shown where analysed (eg. not applicable for ATM alone in combination cohorts)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | NA L | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part A: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | NA L | — |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | 13.8 L | Geometric Coefficient of Variation 10.4 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | 19.0 L | Geometric Coefficient of Variation 15.3 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | 20.1 L | Geometric Coefficient of Variation 10 |
| Part A: Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | 13.4 L | Geometric Coefficient of Variation 16.3 |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | NA L | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part B: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | NA L | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | 22.8 L | Geometric Coefficient of Variation 15.6 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | 15.4 L | Geometric Coefficient of Variation 13.3 |
| Part B: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | 22.2 L | Geometric Coefficient of Variation 10.6 |
| Part B: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | 15.1 L | Geometric Coefficient of Variation 5.2 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | 12.5 L | Geometric Coefficient of Variation 14.9 |
| Part B: Cohort 3 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | 20.0 L | Geometric Coefficient of Variation 18.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | 13.7 L | Geometric Coefficient of Variation 11.9 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | 23.5 L | Geometric Coefficient of Variation 15.5 |
| Part B: Cohort 4 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | 15.6 L | Geometric Coefficient of Variation 18.9 |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part B: Cohort 5 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | 25.2 L | Geometric Coefficient of Variation 26 |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | NA L | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part C: Placebo | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | NA L | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | NA L | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |
| Part C: Cohort 1 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | NA L | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM alone | NA L | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - ATM in comination | NA L | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI in comination | NA L | — |
| Part C: Cohort 2 Drug | PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Vss (L) - AVI alone | NA L | — |