Pharmacokinetic Study of Aztreonam-Avibactam in Severe Renal Impairment

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

11 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-08-10

Study Completion Date

2021-10-18

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.

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Detailed Description

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Conditions

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Renal Insufficiency

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

OTHER

Blinding Strategy

NONE

Study Groups

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Cohort 1

Normal renal function

Group Type EXPERIMENTAL

Aztreonam-Avibactam

Intervention Type DRUG

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

Cohort 2

Severe renal impairment (not on dialysis)

Group Type EXPERIMENTAL

Aztreonam-Avibactam

Intervention Type DRUG

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

Interventions

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Aztreonam-Avibactam

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

Intervention Type DRUG

Aztreonam-Avibactam

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

Intervention Type DRUG

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
* 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
* 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

Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes