A Phase 1, single center, single arm, open-label study to assess the PK, safety and tolerability of Aztreonam-Avibactam after single and repeated IV infusion of doses in healthy Chinese participants.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
12
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
Huashan Hospital Fudan University
Shanghai, Shanghai Municipality, China
Maximum Observed Plasma Concentration (Cmax) on Day 1 & 4 of Aztreonam
Cmax was the maximum observed plasma concentration and was directly observed from data. Concentration values below the lower limit of quantification (LLQ) were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Maximum Observed Plasma Concentration (Cmax) on Day 1 & 4 of Avibactam
Cmax was the maximum observed plasma concentration and was directly observed from data. Concentration values below the lower limit of quantification (LLQ) were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Area Under the Plasma Concentration-Time Profile From Time 0 to 6 Hours (AUC6) on Day 1 of Aztreonam
The area under the plasma drug concentration-time curve (AUC) was estimated from time 0 to 6 hours post dose. AUC6 was computed using the Linear/Log trapezoidal method. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1
Area Under the Plasma Concentration-Time Profile From Time 0 to 6 Hours (AUC6) on Day 1 of Avibactam
The area under the plasma drug concentration-time curve (AUC) was estimated from time 0 to 6 hours post dose. AUC6 was computed using the Linear/Log trapezoidal method. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1
Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) on Day 1 & 4 of Aztreonam
AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. The geometric coefficient of variation is expressed in percentage.
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Time frame: Post dose on day 1 and day 4
Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) on Day 1 & 4 of Avibactam
AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) on Day 1 & 4 of Aztreonam
AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) on Day 1 & 4 of Avibactam
AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) on Day 1 & 4 of Aztreonam
AUCinf was defined as area under the plasma concentration-time curve from time zero to infinity. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) on Day 1 & 4 of Avibactam
AUCinf was defined as area under the plasma concentration-time curve from time zero to infinity. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the End of the Dosing Interval (τ), Where τ=6 Hours (AUCtau) on Day 4 of Aztreonam
AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the End of the Dosing Interval (τ), Where τ=6 Hours (AUCtau) on Day 4 of Avibactam
AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Total Daily Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours at Steady-State (AUC24,ss) on Day 4 of Aztreonam
AUC24,ss was defined as total daily area under the plasma concentration-time profile from time 0 to 24 hours at steady-state. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Total Daily Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours at Steady-State (AUC24,ss) on Day 4 of Avibactam
AUC24,ss was defined as total daily area under the plasma concentration-time profile from time 0 to 24 hours at steady-state. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Renal Clearance (CLr) on Day 1 & 4 of Aztreonam
CLr was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Renal Clearance (CLr) on Day 1 & 4 of Avibactam
CLr was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Terminal Elimination Half-Life (T1/2) on Day 1 & 4 of Aztreonam
Plasma terminal elimination half-life (T1/2) is the time measured for the plasma concentration to decrease by one half at the terminal phase.
Time frame: Post dose on day 1 and day 4
Terminal Elimination Half-Life (T1/2) on Day 1 & 4 of Avibactam
Plasma terminal elimination half-life (T1/2) is the time measured for the plasma concentration to decrease by one half at the terminal phase.
Time frame: Post dose on day 1 and day 4
Apparent Volume of Distribution at Steady-State (Vss) on Day 1 & 4 of Aztreonam
Apparent volume of distribution (Vz) was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss was the Vz at steady-state. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Apparent Volume of Distribution at Steady-State (Vss) on Day 1 & 4 of Avibactam
Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss was the Vz at steady-state. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Apparent Volume of Distribution During Terminal Phase (Vz) on Day 1 & 4 of Aztreonam
Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Apparent Volume of Distribution During Terminal Phase (Vz) on Day 1 & 4 of Avibactam
Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Clearance (CL) on Day 1 & 4 of Aztreonam
CL was a quantitative measure of the rate at which a drug substance was removed from the body. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Clearance (CL) on Day 1 & 4 of Avibactam
CL was a quantitative measure of the rate at which a drug substance was removed from the body. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 1 and day 4
Time of Observed Maximum Plasma Concentration (Tmax) on Day 1 & 4 of Aztreonam
Tmax was defined as time to reach maximum observed plasma concentration.
Time frame: Post dose on day 1 and day 4
Time of Observed Maximum Plasma Concentration (Tmax) on Day 1 & 4 of Avibactam
Tmax was defined as time to reach maximum observed plasma concentration.
Time frame: Post dose on day 1 and day 4
Accumulation Ratio for Cmax (Rac,Cmax) on Day 4 of Aztreonam
Accumulation ratio based on maximum plasma concentration (Rac,cmax) was calculated as: Rac,Cmax = Cmax at steady state (Day 4) divided by Cmax at first dose (Day 1). The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Accumulation Ratio for Cmax (Rac,Cmax) on Day 4 of Avibactam
Accumulation ratio based on maximum plasma concentration (Rac,cmax) was calculated as: Rac,Cmax = Cmax at steady state (Day 4) divided by Cmax at first dose (Day 1). The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Accumulation Ratio for AUCτ Following Multiple Dosing (Rac) on Day 4 of Aztreonam
Rac was obtained from AUCtau at steady state (Day 4) divided by AUCtau after single dose (Day 1). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Accumulation Ratio for AUCτ Following Multiple Dosing (Rac) on Day 4 of Avibactam
Rac was obtained from AUCtau at steady state (Day 4) divided by AUCtau after single dose (Day 1). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage.
Time frame: Post dose on day 4
Number of Participants With an Adverse Event (AE)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
Time frame: From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months)
Number of Participants With Abnormal Vital Signs
Criteria for vital signs abnormalities: increase or decrease from baseline in supine Systolic Blood Pressure (SBP) \>=30 mm Hg and increase or decrease from baseline in supine Diastolic Blood Pressure (DBP) \>=20 mm Hg.
Time frame: From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months)
Number of Participants With Abnormal Electrocardiograms (ECGs)
ECG categorical summarization criteria: 1. PR interval (the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization): a) greater than or equal to (\>=) 300 millisecond (msec), b) \>=25% increase when baseline is \> 200 msec or \>=50% increase when baseline is less than or equal to (\<=) 200 msec. 2\. QRS duration (time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization): a) \>=140 msec, b) \>=50% increase from baseline. 3\. QTcF interval (QT corrected using the Fridericia formula): a) \>450 msec and \<=480 msec, b) \>480 msec and \<=500 msec, c) \>500 msec, d) \>30 msec and \<=60 msec increase from baseline, e) \>60 msec increase from baseline.
Time frame: From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months)
Number of Participants With Abnormal Laboratory Assessments
Following laboratory parameters were assessed against pre-defined abnormality criteria: hematology (basophils); clinical chemistry (urate); urinalysis (urine hemoglobin, nitrite, urine erythrocytes).
Time frame: From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months)