Pharmacokinetic Study of Aztreonam-Avibactam in Severe Renal Impairment
Condition: Renal Insufficiency
MeSH terms: Renal Insufficiency
Intervention: Aztreonam-Avibactam; Aztreonam-Avibactam
Intervention description: 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; 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 MeSH terms: Aztreonam; Avibactam
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Infection

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.
    

Eligibility criteria:

        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