Pharmacokinetic Study of Aztreonam-Avibactam in Severe Renal Impairment

NCT04486625 | Completed Phase 1 Results FDA Drug

• 1 other identifier: C3601006
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

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.

Conditions

Renal Insufficiency

Keywords

Infection

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (25)

• Area Under the Plasma Concentration-time Profile From Time 0 to Time Tau (The Dosing Interval)(AUC0-tau) of ATM

  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

  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

  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

  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

  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.

Study Arms (2)

Cohort 1

EXPERIMENTAL

Normal renal function

Drug: Aztreonam-Avibactam

Cohort 2

EXPERIMENTAL

Severe renal impairment (not on dialysis)

Drug: Aztreonam-Avibactam

Interventions

Aztreonam-Avibactam 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 1

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Pfizer: lead

Study Sites (1)

Prism Research LLC dba Nucleus Network

Saint Paul, Minnesota, 55114, United States

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Renal Insufficiency; Infections

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2020
• First Posted: July 24, 2020
• Study Start: August 10, 2020
• Primary Completion: September 20, 2021
• Study Completion: October 18, 2021
• Last Updated: July 28, 2023
• Results First Posted: July 28, 2023

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)