Pharmacokinetic Study of Aztreonam-Avibactam in Severe Renal Impairment

Study Overview
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Brief Summary
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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.

Official Title
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AN OPEN-LABEL, PARALLEL-GROUP, PHARMACOKINETIC STUDY OF MULTIPLE INTRAVENOUS DOSES OF AZTREONAM AND AVIBACTAM IN SUBJECTS WITH SEVERE RENAL IMPAIRMENT AND NORMAL RENAL FUNCTION

Conditions
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Renal Insufficiency

Intervention / Treatment
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* Drug: Aztreonam-Avibactam
* Drug: Aztreonam-Avibactam


Participation Criteria
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Eligibility Criteria
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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 Exclusion criteria: Subjects with Severe Renal Impairment Any significant hepatic, cardiac, or pulmonary disease Renal allograft recipients or subjects who are clinically nephrotic Subjects requiring dialysis Screening supine 12-lead ECG demonstrating QT interval corrected by Fridericia's formula (QTcF) >470 msec or a QRS interval >120 msec Screening supine BP >/=180 millimeters of mercury (mm Hg) (systolic) or >/=110 mm Hg (diastolic), on a single measurement (confirmed by a single repeat, if necessary) following at least 5 minutes of rest Exclusion criteria: Subjects with Normal Renal Function Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including clinically relevant and significant drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) Screening supine 12-lead ECG demonstrating QTcF >450 msec or a QRS interval >120 msec Screening supine BP >/=140 mm Hg (systolic) or >/=90 mm Hg (diastolic), following at least 5 minutes of supine rest

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Normal renal function | Drug: Aztreonam-Avibactam<br>* 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<br>|
| Experimental: Cohort 2<br>Severe renal impairment (not on dialysis) | Drug: Aztreonam-Avibactam<br>* 675/225 mg ATM/AVI loading infusion, followed by 675/225 mg ATM/AVI extended loading infusion, then 675/225 mg ATM/AVI maintenance dose infusion every 8 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 
| Maximum Plasma Concentration (Cmax) of ATM | The Cmax of ATM was observed directly from data. | 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 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). | 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. | 
| Cmax of AVI | The Cmax of AVI was observed directly from data. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 
| Time for Cmax (Tmax) of ATM | The Tmax was observed directly from data as time of first occurrence. | 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. | 
| 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). | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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). | 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. | 
| 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). | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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). | 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. | 
| 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 | 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. | 
| Tmax of AVI | The Tmax was observed directly from data as time of first occurrence. | 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. | 
| 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). | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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). | 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. | 
| 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). | 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 of AVI | Vss was calculated by CL*MRT, where CL was clearance and MRT was mean residence time. | 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. | 
| 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). | 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. | 
| 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). | 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. | 
| 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. | Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days). | 
| 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. | Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days). | 
| 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. | Days 1 to 3 | 
| 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. | Days 1 to 3 | 
| 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. | Days 1 to 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infection