Renal Insufficiency
Conditions
Keywords
Infection
Brief summary
This Phase 1 study is being conducted to evaluate the effect of severe renal impairment on the PK, safety and tolerability of Aztreonam-Avibactam. Results from this study along with previous renal impairment data from each of the Aztreonam-Avibactam components will be used to confirm the proposed dosing adjustment in severe renal impairment which was based on modelling/simulation.
Interventions
500/167 mg ATM/AVI loading infusion, followed by 1500/500 mg ATM/AVI extended loading infusion, then 1500/500 mg ATM/AVI maintenance dose infusion every 6 hours
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy female subjects and/or male subjects between the ages of 18 and 75 years, inclusive. Male and female subjects of childbearing potential must agree to use highly effective method(s) of contraception * Body mass index (BMI) of 17.5 to 40.5 kg/m2; and a total body weight \>50 kg (110 lb) * Stable renal function defined as \</=25% difference between 2 measurements of eGFR obtained on 2 separate occasions during the screening period that are at least 72 hours but no more than 14 days apart Specific Requirements for Healthy Subjects with Normal Renal Function * Normal renal function (eGFR\>/= 80 mL/min) at Screening based on the Day -2 value, using the MDRD formula adjusting for BSA * Demographically comparable to the group of subjects with severe impaired renal function Specific Requirements for Subjects with Severe Renal Impairment * Good general health commensurate with the population with chronic kidney disease. * Documented severe renal impairment indicated by eGFR \>15 -\</=30 mL/min but not requiring hemodialysis, using the MDRD formula adjusting for BSA
Exclusion criteria
* Positive urine drug test * History of regular alcohol use (within 6 months) exceeding 7 drinks/week for female or 14 drinks/week for male subjects * Treatment with an investigational product within 30 days or 5 half-lives preceding the first dose of investigational product (whichever is longer) * Subjects with abnormalities in clinical laboratory tests (AST, ALT, Total bilirubin, aPTT, PT, INR) at Screening * Pregnant females; breastfeeding females; fertile male subjects and female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception * Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of investigational product. For subjects with severe renal impairment, concomitant medications may be given if considered necessary for the subject welfare (eg, standard therapy for underlying diseases), are not contraindicated with the study drug, and are unlikely to interfere with the PK/PD response of the study drug. Use of oral anticoagulants and potent inhibitors of OAT1 and/or OAT3 (eg, probenecid) are prohibited in all subjects. * Blood donation (excluding plasma donations) of approximately 1 pint or more within 60 days prior to dosing * History of sensitivity to heparin or heparin-induced thrombocytopenia * History of serious allergy, hypersensitivity or any serious reaction to aztreonam, carbapenem, monobactam or other beta-lactam antibiotics, avibactam, or any of the excipients of the respective (investigational) medicinal products * History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C * Other acute or chronic medical or psychiatric condition * Past or current history of epilepsy or seizure disorders excluding febrile seizures of childhood
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Daily Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours at Steady-state (AUC0-24,ss) of Aztreonam (ATM) | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | AUC0-24,ss of ATM in Cohort 1 was calculated by 4\*AUC0-tau (tau = 6 hours), where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). AUC0-24,ss of ATM in Cohort 2 was calculated by 3\*AUC0-tau (tau = 8 hours), where AUC0-tau was area under the plasma concentration-time profile from time 0 to time tau (the dosing interval). |
| Maximum Plasma Concentration (Cmax) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Cmax of ATM was observed directly from data. |
| AUC0-24,ss of Avibactam (AVI) | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | AUC0-24,ss of AVI in Cohort 1 was calculated by 4\*AUC0-tau (tau = 6 hours), where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). AUC0-24,ss of AVI in Cohort 2 was calculated by 3\*AUC0-tau (tau = 8 hours), where AUC0-tau was area under the plasma concentration-time profile from time 0 to time tau (the dosing interval). |
| Cmax of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Cmax of AVI was observed directly from data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Elimination Half-life (t1/2) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The t1/2 was calculated by loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. |
| Clearance (CL) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The CL was calculated by dose/AUC0-tau, where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| Renal Clearance (CLr) of ATM | In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion. | The CLr was calculated by Ae0-tau/AUC0-tau, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau and AUC0-tau was area under the plasma concentration time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| Apparent Volume of Distribution (Vz) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Vz was calculated by dose/(AUC0-tau\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve and AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for the normal renal function group (Cohort 1) and 8 hours for the severe renal impairment group (Cohort 2). |
| Cumulative Amount of Drug Recovered Unchanged in Urine up to Time Tau (Ae0-tau) of ATM | In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion. | The Ae0-tau was the sum of (urine concentration\*sample volume). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| Percent of Dose Recovered Unchanged in Urine up to Time Tau (Ae0-tau%) of ATM | In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion. | The Ae0-tau was calculated by 100\*Ae0-tau/dose, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| AUC0-tau of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The UC0-tau was calculated by linear/log trapezoidal method. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).A |
| Tmax of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Tmax was observed directly from data as time of first occurrence. |
| Ctau of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Ctau was observed directly from data. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| t1/2 of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The t1/2 was calculated by loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. |
| Area Under the Plasma Concentration-time Profile From Time 0 to Time Tau (The Dosing Interval)(AUC0-tau) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The AUC0-tau was calculated by linear/log trapezoidal method. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| CLr of AVI | In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion. | The CLr was calculated by Ae0-tau/AUC0-tau, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau and AUC0-tau was area under the plasma concentration time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| Vz of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Vz was calculated by dose/(AUC0-tau\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve and AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for the normal renal function group (Cohort 1) and 8 hours for the severe renal impairment group (Cohort 2). |
| Vss of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | Vss was calculated by CL\*MRT, where CL was clearance and MRT was mean residence time. |
| Ae0-tau of AVI | In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion. | The Ae0-tau was the sum of (urine concentration\*sample volume). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| Ae0-tau% of AVI | In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion. | The Ae0-tau was calculated by 100\*Ae0-tau/dose, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days). | An adverse event (AE) is any untoward medical occurrence in a study participant administered a product; the event need not necessarily have a causal relationship with the treatment or usage. A serious adverse event is any untoward medical occurrence at any dose that: (1) results in death; (2) is life threatening (immediate risk of death); (3) requires inpatient hospitalization or prolongation of existing hospitalization; (4) results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); (5) results in congenital anomaly/birth defect; or that is considered to be an important medical event. Treatment-emergent are events between first dose of study medication and up to at least 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A severe AE is defined as a event interferes significantly with participant's usual function. |
| Number of Participants With TEAEs (Treatment-related) | Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days). | An adverse event (AE) is any untoward medical occurrence in a study participant administered a product; the event attributed to the study medication. A serious AE is any untoward medical occurrence at any dose that: (1) results in death; (2) is life threatening (immediate risk of death); (3) requires inpatient hospitalization or prolongation of existing hospitalization; (4) results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); (5) results in congenital anomaly/birth defect; or that is considered to be an important medical event. Treatment-emergent are events between first dose of study medication and up to at least 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A severe AE is defined as a event interferes significantly with participant's usual function. |
| Number of Participants With Categorical Post-Baseline Vital Signs Data | Days 1 to 3 | Categorical post-baseline vital signs included: (1) pulse rate: value less than (\<) 40 beats per minute (bpm), lager than (\>) 120 bpm; (2) supine diastolic blood pressure (DBP): value \<50 mmHg, change of more than or equal to (\>=) 20 mmHg increase, change of \>=20 mmHg decrease; (3) supine systolic blood pressure (SBP): value \<90 mmHg, change of \>=30 mmHg increase, change of \>=30 mmHg decrease. |
| Number of Participants With Abnormal Electrocardiogram (ECG) | Days 1 to 3 | Criteria for ECG abnormalities: maximum QT interval \>500 milliseconds (msec); maximum QTc interval of \>=450 msec to less than or equal to (\<=) 480 msec, \>480 msec, and \>500 msec and a maximum change of \<30 change\<=60 or \>60 msec from baseline; maximum QTcF (Fridericia's Correction) interval of \>=450 msec to \<=480 msec, \>480 msec, and \>500 msec and a maximum change of \<30 change\<=60 or \>60 msec from baseline. |
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Days 1 to 3 | Following laboratory parameters were abnormal (without regard to baseline abnormality): hemoglobin, hematocrit, erythrocytes, lymphocytes, neutrophils, activated partial thromboplastin time, protein, urea nitrogen, creatinine, urate, urine glucose, and urine protein. |
| CL of AVI | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The CL was calculated by dose/AUC0-tau, where AUC0-tau was area under the plasma concentration-time profile from time 0 to to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
| Time for Cmax (Tmax) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Tmax was observed directly from data as time of first occurrence. |
| Apparent Volume of Distribution at Steady-state (Vss) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | Vss was calculated by CL\*MRT, where CL was clearance and MRT was mean residence time. |
| Observed Plasma Concentration at the End of the Dosing Interval (Tau) (Ctau) of ATM | Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3. | The Ctau was observed directly from data. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2). |
Countries
United States
Participant flow
Pre-assignment details
This was a Phase 1, open-label, parallel-group study where an intravenous (IV) loading dose (30-minute infusion) followed by multiple IV doses (3-hour infusion) of aztreonam-avibactam (ATM-AVI) were administered to participants with severe renal impairment (not on dialysis) (Cohort 1) and to healthy participants with normal renal function (Cohort 2).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Normal Renal Function Participants with normal renal function received 30-minute IV loading dose infusion (500/167 mg aztreonam \[ATM\]/avibactam \[AVI\]), followed by 3-hour IV extended loading infusion (1500/500 mg ATM/AVI), then 3-hour 1500/500 mg ATM/AVI maintenance dose infusion every 6 hours on Days 1 to 3. | 6 |
| Cohort 2: Severe Renal Impairment Participants with severe renal impairment (not on dialysis) received 30-minute IV loading dose infusion (675/255 mg aztreonam \[ATM\]/avibactam \[AVI\]), followed by 3-hour IV extended loading infusion (675/255 mg ATM/AVI), then 3-hour 675/255 mg ATM/AVI maintenance dose infusion every 8 hours on Days 1 to 3. | 5 |
| Total | 11 |
Baseline characteristics
| Characteristic | Cohort 1: Normal Renal Function | Cohort 2: Severe Renal Impairment | Total |
|---|---|---|---|
| Age, Continuous Mean | 61.0 Years STANDARD_DEVIATION 1.67 | 67.8 Years STANDARD_DEVIATION 8.56 | 64.1 Years STANDARD_DEVIATION 6.58 |
| Body Weight | 98.65 kilogram (kg) STANDARD_DEVIATION 6.354 | 101.06 kilogram (kg) STANDARD_DEVIATION 13.068 | 99.75 kilogram (kg) STANDARD_DEVIATION 9.491 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 |
| other Total, other adverse events | 2 / 6 | 3 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 |
Outcome results
Primary
AUC0-24,ss of Avibactam (AVI)
AUC0-24,ss of AVI in Cohort 1 was calculated by 4\*AUC0-tau (tau = 6 hours), where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). AUC0-24,ss of AVI in Cohort 2 was calculated by 3\*AUC0-tau (tau = 8 hours), where AUC0-tau was area under the plasma concentration-time profile from time 0 to time tau (the dosing interval).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | AUC0-24,ss of Avibactam (AVI) | 164.8 ug*hr/mL | Geometric Coefficient of Variation 18 |
| Cohort 2: Severe Renal Impairment | AUC0-24,ss of Avibactam (AVI) | 204.6 ug*hr/mL | Geometric Coefficient of Variation 20 |
90% CI: [100.18, 153.97]
Primary
Cmax of AVI
The Cmax of AVI was observed directly from data.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Cmax of AVI | 11.08 ug/mL | Geometric Coefficient of Variation 14 |
| Cohort 2: Severe Renal Impairment | Cmax of AVI | 11.35 ug/mL | Geometric Coefficient of Variation 14 |
90% CI: [87.55, 119.83]
Primary
Maximum Plasma Concentration (Cmax) of ATM
The Cmax of ATM was observed directly from data.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Maximum Plasma Concentration (Cmax) of ATM | 57.34 Microgram per milliliter (ug/mL) | Geometric Coefficient of Variation 13 |
| Cohort 2: Severe Renal Impairment | Maximum Plasma Concentration (Cmax) of ATM | 43.34 Microgram per milliliter (ug/mL) | Geometric Coefficient of Variation 11 |
90% CI: [66.1, 86.43]
Primary
Total Daily Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours at Steady-state (AUC0-24,ss) of Aztreonam (ATM)
AUC0-24,ss of ATM in Cohort 1 was calculated by 4\*AUC0-tau (tau = 6 hours), where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). AUC0-24,ss of ATM in Cohort 2 was calculated by 3\*AUC0-tau (tau = 8 hours), where AUC0-tau was area under the plasma concentration-time profile from time 0 to time tau (the dosing interval).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Total Daily Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours at Steady-state (AUC0-24,ss) of Aztreonam (ATM) | 922.9 Microgram*hour per milliliter (ug*hr/mL) | Geometric Coefficient of Variation 16 |
| Cohort 2: Severe Renal Impairment | Total Daily Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours at Steady-state (AUC0-24,ss) of Aztreonam (ATM) | 733.5 Microgram*hour per milliliter (ug*hr/mL) | Geometric Coefficient of Variation 16 |
90% CI: [66.52, 94.96]
Secondary
Ae0-tau of AVI
The Ae0-tau was the sum of (urine concentration\*sample volume). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Ae0-tau of AVI | 465.6 mg | Geometric Coefficient of Variation 11 |
| Cohort 2: Severe Renal Impairment | Ae0-tau of AVI | 270.0 mg | Geometric Coefficient of Variation 17 |
Secondary
Ae0-tau% of AVI
The Ae0-tau was calculated by 100\*Ae0-tau/dose, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Ae0-tau% of AVI | 93.19 Percent of dose | Geometric Coefficient of Variation 11 |
| Cohort 2: Severe Renal Impairment | Ae0-tau% of AVI | 119.9 Percent of dose | Geometric Coefficient of Variation 17 |
Secondary
Apparent Volume of Distribution at Steady-state (Vss) of ATM
Vss was calculated by CL\*MRT, where CL was clearance and MRT was mean residence time.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Apparent Volume of Distribution at Steady-state (Vss) of ATM | 23.70 L | Geometric Coefficient of Variation 29 |
| Cohort 2: Severe Renal Impairment | Apparent Volume of Distribution at Steady-state (Vss) of ATM | 18.46 L | Geometric Coefficient of Variation 19 |
Secondary
Apparent Volume of Distribution (Vz) of ATM
The Vz was calculated by dose/(AUC0-tau\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve and AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for the normal renal function group (Cohort 1) and 8 hours for the severe renal impairment group (Cohort 2).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Apparent Volume of Distribution (Vz) of ATM | 24.25 Liters (L) | Geometric Coefficient of Variation 23 |
| Cohort 2: Severe Renal Impairment | Apparent Volume of Distribution (Vz) of ATM | 18.79 Liters (L) | Geometric Coefficient of Variation 21 |
Secondary
Area Under the Plasma Concentration-time Profile From Time 0 to Time Tau (The Dosing Interval)(AUC0-tau) of ATM
The AUC0-tau was calculated by linear/log trapezoidal method. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Area Under the Plasma Concentration-time Profile From Time 0 to Time Tau (The Dosing Interval)(AUC0-tau) of ATM | 230.8 ug*hr/mL | Geometric Coefficient of Variation 16 |
| Cohort 2: Severe Renal Impairment | Area Under the Plasma Concentration-time Profile From Time 0 to Time Tau (The Dosing Interval)(AUC0-tau) of ATM | 244.3 ug*hr/mL | Geometric Coefficient of Variation 16 |
Secondary
AUC0-tau of AVI
The UC0-tau was calculated by linear/log trapezoidal method. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).A
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | AUC0-tau of AVI | 41.19 ug*hr/mL | Geometric Coefficient of Variation 18 |
| Cohort 2: Severe Renal Impairment | AUC0-tau of AVI | 68.31 ug*hr/mL | Geometric Coefficient of Variation 20 |
Secondary
Clearance (CL) of ATM
The CL was calculated by dose/AUC0-tau, where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Clearance (CL) of ATM | 6.499 Liters per hour (L/hr) | Geometric Coefficient of Variation 16 |
| Cohort 2: Severe Renal Impairment | Clearance (CL) of ATM | 2.761 Liters per hour (L/hr) | Geometric Coefficient of Variation 16 |
Secondary
CL of AVI
The CL was calculated by dose/AUC0-tau, where AUC0-tau was area under the plasma concentration-time profile from time 0 to to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | CL of AVI | 12.16 L/hr | Geometric Coefficient of Variation 18 |
| Cohort 2: Severe Renal Impairment | CL of AVI | 3.295 L/hr | Geometric Coefficient of Variation 20 |
Secondary
CLr of AVI
The CLr was calculated by Ae0-tau/AUC0-tau, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau and AUC0-tau was area under the plasma concentration time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | CLr of AVI | 11.30 L/hr | Geometric Coefficient of Variation 20 |
| Cohort 2: Severe Renal Impairment | CLr of AVI | 3.948 L/hr | Geometric Coefficient of Variation 36 |
Secondary
Ctau of AVI
The Ctau was observed directly from data. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Ctau of AVI | 3.100 ug/mL | Geometric Coefficient of Variation 24 |
| Cohort 2: Severe Renal Impairment | Ctau of AVI | 5.597 ug/mL | Geometric Coefficient of Variation 39 |
Secondary
Cumulative Amount of Drug Recovered Unchanged in Urine up to Time Tau (Ae0-tau) of ATM
The Ae0-tau was the sum of (urine concentration\*sample volume). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Cumulative Amount of Drug Recovered Unchanged in Urine up to Time Tau (Ae0-tau) of ATM | 1047 Milligram (mg) | Geometric Coefficient of Variation 11 |
| Cohort 2: Severe Renal Impairment | Cumulative Amount of Drug Recovered Unchanged in Urine up to Time Tau (Ae0-tau) of ATM | 361.2 Milligram (mg) | Geometric Coefficient of Variation 19 |
Secondary
Number of Participants With Abnormal Electrocardiogram (ECG)
Criteria for ECG abnormalities: maximum QT interval \>500 milliseconds (msec); maximum QTc interval of \>=450 msec to less than or equal to (\<=) 480 msec, \>480 msec, and \>500 msec and a maximum change of \<30 change\<=60 or \>60 msec from baseline; maximum QTcF (Fridericia's Correction) interval of \>=450 msec to \<=480 msec, \>480 msec, and \>500 msec and a maximum change of \<30 change\<=60 or \>60 msec from baseline.
Time frame: Days 1 to 3
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | QTc interval value >500 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | 450 msec<= QTcF interval value <=480 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | QTc interval value >480 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | QTcF interval value >480 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | 30 msec< QTc interval change <=60 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | QTcF interval value >500 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | 450 msec<= QTc interval value <=480 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | 30 msec< QTcF interval change <=60 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | QTc interval change >60 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | QTcF interval change >60 msec | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Abnormal Electrocardiogram (ECG) | QT interval value > 500 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | QTcF interval change >60 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | QT interval value > 500 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | 450 msec<= QTc interval value <=480 msec | 2 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | QTc interval value >480 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | QTc interval value >500 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | 30 msec< QTc interval change <=60 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | QTc interval change >60 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | 450 msec<= QTcF interval value <=480 msec | 2 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | QTcF interval value >480 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | QTcF interval value >500 msec | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) | 30 msec< QTcF interval change <=60 msec | 0 Participants |
Secondary
Number of Participants With Categorical Post-Baseline Vital Signs Data
Categorical post-baseline vital signs included: (1) pulse rate: value less than (\<) 40 beats per minute (bpm), lager than (\>) 120 bpm; (2) supine diastolic blood pressure (DBP): value \<50 mmHg, change of more than or equal to (\>=) 20 mmHg increase, change of \>=20 mmHg decrease; (3) supine systolic blood pressure (SBP): value \<90 mmHg, change of \>=30 mmHg increase, change of \>=30 mmHg decrease.
Time frame: Days 1 to 3
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Pulse rate <40 bpm | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Pulse rate >120 bpm | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine DBP <50 mmHg | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine DBP change >=20 mmHg increase | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine DBP change >=20 mmHg decrease | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine SBP <90 mmHg | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine SBP change >=30 mmHg increase | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine SBP change >=30 mmHg decrease | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine SBP change >=30 mmHg decrease | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Pulse rate <40 bpm | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine DBP change >=20 mmHg decrease | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Pulse rate >120 bpm | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine SBP change >=30 mmHg increase | 1 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine DBP <50 mmHg | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine SBP <90 mmHg | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Categorical Post-Baseline Vital Signs Data | Supine DBP change >=20 mmHg increase | 0 Participants |
Secondary
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)
Following laboratory parameters were abnormal (without regard to baseline abnormality): hemoglobin, hematocrit, erythrocytes, lymphocytes, neutrophils, activated partial thromboplastin time, protein, urea nitrogen, creatinine, urate, urine glucose, and urine protein.
Time frame: Days 1 to 3
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Hemoglobin (gram per deciliter [g/dL]) <0.8*lower limit of normal (LLN) | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Hematocrit (%) <0.8*LLN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Erythrocytes (10^6 per cubic millimeter [10^6/mm^3]) <0.8*LLN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Lymphocytes (10^3 per cubic millimeter [10^3/mm^3]) <0.8*LLN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Neutrophils (10^3/mm^3) >1.2*upper limit of normal (ULN) | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Activated partial thromboplastin time (second) >1.1*ULN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Protein (g/dL) <0.8*LLN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urea Nitrogen (milligram per deciliter [mg/dL]) >1.3*ULN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Creatinine (mg/dL) >1.3*ULN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urate (mg/dL) >1.2*ULN | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urine glucose (mg/dL) >=1 | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urine protein (mg/dL) >=1 | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urine glucose (mg/dL) >=1 | 3 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Hemoglobin (gram per deciliter [g/dL]) <0.8*lower limit of normal (LLN) | 3 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Protein (g/dL) <0.8*LLN | 1 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Hematocrit (%) <0.8*LLN | 3 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urate (mg/dL) >1.2*ULN | 3 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Erythrocytes (10^6 per cubic millimeter [10^6/mm^3]) <0.8*LLN | 4 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urea Nitrogen (milligram per deciliter [mg/dL]) >1.3*ULN | 5 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Lymphocytes (10^3 per cubic millimeter [10^3/mm^3]) <0.8*LLN | 1 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Urine protein (mg/dL) >=1 | 1 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Neutrophils (10^3/mm^3) >1.2*upper limit of normal (ULN) | 1 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Creatinine (mg/dL) >1.3*ULN | 5 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Activated partial thromboplastin time (second) >1.1*ULN | 1 Participants |
Secondary
Number of Participants With TEAEs (Treatment-related)
An adverse event (AE) is any untoward medical occurrence in a study participant administered a product; the event attributed to the study medication. A serious AE is any untoward medical occurrence at any dose that: (1) results in death; (2) is life threatening (immediate risk of death); (3) requires inpatient hospitalization or prolongation of existing hospitalization; (4) results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); (5) results in congenital anomaly/birth defect; or that is considered to be an important medical event. Treatment-emergent are events between first dose of study medication and up to at least 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A severe AE is defined as a event interferes significantly with participant's usual function.
Time frame: Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days).
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Number of Participants With TEAEs (Treatment-related) | Participants with AEs | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With TEAEs (Treatment-related) | Participants with serious AEs | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With TEAEs (Treatment-related) | Participants with severe AEs | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With TEAEs (Treatment-related) | Participants discontinued from study due to AEs | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With TEAEs (Treatment-related) | Participants discontinued study drug due to AEs and continue study | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With TEAEs (Treatment-related) | Participants with dose reduced or temporary discontinuation due to AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With TEAEs (Treatment-related) | Participants discontinued study drug due to AEs and continue study | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With TEAEs (Treatment-related) | Participants with AEs | 3 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With TEAEs (Treatment-related) | Participants discontinued from study due to AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With TEAEs (Treatment-related) | Participants with serious AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With TEAEs (Treatment-related) | Participants with dose reduced or temporary discontinuation due to AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With TEAEs (Treatment-related) | Participants with severe AEs | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality)
An adverse event (AE) is any untoward medical occurrence in a study participant administered a product; the event need not necessarily have a causal relationship with the treatment or usage. A serious adverse event is any untoward medical occurrence at any dose that: (1) results in death; (2) is life threatening (immediate risk of death); (3) requires inpatient hospitalization or prolongation of existing hospitalization; (4) results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); (5) results in congenital anomaly/birth defect; or that is considered to be an important medical event. Treatment-emergent are events between first dose of study medication and up to at least 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A severe AE is defined as a event interferes significantly with participant's usual function.
Time frame: Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days).
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with AEs | 2 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with serious AEs | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with severe AEs | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants discontinued from study due to AEs | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants discontinued study drug due to AEs and continue study | 0 Participants |
| Cohort 1: Normal Renal Function | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with dose reduced or temporary discontinuation due to AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants discontinued study drug due to AEs and continue study | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with AEs | 3 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants discontinued from study due to AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with serious AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with dose reduced or temporary discontinuation due to AEs | 0 Participants |
| Cohort 2: Severe Renal Impairment | Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality) | Participants with severe AEs | 0 Participants |
Secondary
Observed Plasma Concentration at the End of the Dosing Interval (Tau) (Ctau) of ATM
The Ctau was observed directly from data. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Observed Plasma Concentration at the End of the Dosing Interval (Tau) (Ctau) of ATM | 21.43 ug/mL | Geometric Coefficient of Variation 19 |
| Cohort 2: Severe Renal Impairment | Observed Plasma Concentration at the End of the Dosing Interval (Tau) (Ctau) of ATM | 18.55 ug/mL | Geometric Coefficient of Variation 24 |
Secondary
Percent of Dose Recovered Unchanged in Urine up to Time Tau (Ae0-tau%) of ATM
The Ae0-tau was calculated by 100\*Ae0-tau/dose, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau. The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Percent of Dose Recovered Unchanged in Urine up to Time Tau (Ae0-tau%) of ATM | 69.68 Percent of dose | Geometric Coefficient of Variation 11 |
| Cohort 2: Severe Renal Impairment | Percent of Dose Recovered Unchanged in Urine up to Time Tau (Ae0-tau%) of ATM | 53.51 Percent of dose | Geometric Coefficient of Variation 19 |
Secondary
Renal Clearance (CLr) of ATM
The CLr was calculated by Ae0-tau/AUC0-tau, where Ae0-tau was cumulative amount of drug recovered unchanged in urine up to time tau and AUC0-tau was area under the plasma concentration time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Time frame: In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Renal Clearance (CLr) of ATM | 4.527 L/hr | Geometric Coefficient of Variation 18 |
| Cohort 2: Severe Renal Impairment | Renal Clearance (CLr) of ATM | 1.477 L/hr | Geometric Coefficient of Variation 23 |
Secondary
t1/2 of AVI
The t1/2 was calculated by loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | t1/2 of AVI | 3.188 Hours | Standard Deviation 0.071391 |
| Cohort 2: Severe Renal Impairment | t1/2 of AVI | 6.524 Hours | Standard Deviation 1.6469 |
Secondary
Terminal Elimination Half-life (t1/2) of ATM
The t1/2 was calculated by loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Terminal Elimination Half-life (t1/2) of ATM | 2.605 Hours | Standard Deviation 0.34944 |
| Cohort 2: Severe Renal Impairment | Terminal Elimination Half-life (t1/2) of ATM | 4.902 Hours | Standard Deviation 1.4286 |
Secondary
Time for Cmax (Tmax) of ATM
The Tmax was observed directly from data as time of first occurrence.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Normal Renal Function | Time for Cmax (Tmax) of ATM | 2.92 Hours |
| Cohort 2: Severe Renal Impairment | Time for Cmax (Tmax) of ATM | 2.92 Hours |
Secondary
Tmax of AVI
The Tmax was observed directly from data as time of first occurrence.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Normal Renal Function | Tmax of AVI | 2.46 Hours |
| Cohort 2: Severe Renal Impairment | Tmax of AVI | 2.92 Hours |
Secondary
Vss of AVI
Vss was calculated by CL\*MRT, where CL was clearance and MRT was mean residence time.
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Vss of AVI | 37.37 L | Geometric Coefficient of Variation 30 |
| Cohort 2: Severe Renal Impairment | Vss of AVI | 27.78 L | Geometric Coefficient of Variation 16 |
Secondary
Vz of AVI
The Vz was calculated by dose/(AUC0-tau\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve and AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). The dosing interval (tau) was 6 hours for the normal renal function group (Cohort 1) and 8 hours for the severe renal impairment group (Cohort 2).
Time frame: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
Population: The analysis population included all participants treated with study medication who had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Renal Function | Vz of AVI | 55.83 L | Geometric Coefficient of Variation 19 |
| Cohort 2: Severe Renal Impairment | Vz of AVI | 30.14 L | Geometric Coefficient of Variation 16 |