Clinical trial NCT04486625: Pharmacokinetic Study of Aztreonam-Avibactam in Severe Renal Impairment
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Insufficiency
Keywords: Infection
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2020-07-24
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.


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

Primary outcomes:
measure: Total Daily Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours at Steady-state (AUC0-24,ss) of Aztreonam (ATM)
timeFrame: 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.
measure: Maximum Plasma Concentration (Cmax) of ATM
timeFrame: 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.
measure: AUC0-24,ss of Avibactam (AVI)
timeFrame: 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.
measure: Cmax of AVI
timeFrame: 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 outcomes:
measure: Area Under the Plasma Concentration-time Profile From Time 0 to Time Tau (The Dosing Interval)(AUC0-tau) of ATM
timeFrame: 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.
measure: Time for Cmax (Tmax) of ATM
timeFrame: 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.
measure: Observed Plasma Concentration at the End of the Dosing Interval (Tau) (Ctau) of ATM
timeFrame: 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.
measure: Terminal Elimination Half-life (t1/2) of ATM
timeFrame: 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.
measure: Clearance (CL) of ATM
timeFrame: 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.
measure: Renal Clearance (CLr) of ATM
timeFrame: 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.
measure: Apparent Volume of Distribution (Vz) of ATM
timeFrame: 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.
measure: Apparent Volume of Distribution at Steady-state (Vss) of ATM
timeFrame: 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.
measure: Cumulative Amount of Drug Recovered Unchanged in Urine up to Time Tau (Ae0-tau) of ATM
timeFrame: 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.
measure: Percent of Dose Recovered Unchanged in Urine up to Time Tau (Ae0-tau%) of ATM
timeFrame: 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.
measure: AUC0-tau of AVI
timeFrame: 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.
measure: Tmax of AVI
timeFrame: 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.
measure: Ctau of AVI
timeFrame: 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.
measure: t1/2 of AVI
timeFrame: 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.
measure: CL of AVI
timeFrame: 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.
measure: CLr of AVI
timeFrame: 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.
measure: Vz of AVI
timeFrame: 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.
measure: Vss of AVI
timeFrame: 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.
measure: Ae0-tau of AVI
timeFrame: 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.
measure: Ae0-tau% of AVI
timeFrame: 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.
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality)
timeFrame: Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days).
measure: Number of Participants With TEAEs (Treatment-related)
timeFrame: Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days).
measure: Number of Participants With Categorical Post-Baseline Vital Signs Data
timeFrame: Days 1 to 3
measure: Number of Participants With Abnormal Electrocardiogram (ECG)
timeFrame: Days 1 to 3
measure: Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)
timeFrame: Days 1 to 3
Other outcomes:
Locations:
city: Saint Paul
country: United States
facility: Prism Research LLC dba Nucleus Network
state: Minnesota
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: