A Study To Assess The Effect Of Linezolid On QTc Interval

Single Dose Safety, Tolerability And Pharmacokinetics Of Escalating Intravenous Doses Of Linezolid Followed By Evaluation Of The Effect Of Single Intravenous Doses Of Linezolid On QTc Interval In Healthy Subjects

The FDA has asked Pfizer to assess the risk of linezolid on QT interval (obtained from ECG readings) which could predispose patients to ventricular arrhythmias. This study is conducted to satisfy this requirement.

Study Overview

• Status: Completed
• Conditions: Bacterial Infections
• Intervention / Treatment: Drug: Placebo; Drug: Linezolid 900 mg; Drug: Linezolid 1200 mg; Drug: Linezolid 600 mg; Drug: Moxifloxacin 400 mg

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 188770
    • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 51 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and female subjects between the ages of 21 and 55 years.
• Body mass Index (BMI) of 18 to 30 kg/m2; and a total body weight > 45 kg (99 lbs).
• An informed consent document signed and dated.

Exclusion Criteria:

• Evidence or history of clinically significant abnormality.
• 12-lead ECG demonstrating QTc >450 msec at Screening.
• Receiving selective serotonin reuptake inhibitors (SSRIs) and/or sympathomimetic agents.
• Abnormal liver function tests.
• A positive urine drug screen, history of excessive alcohol and tobacco use.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Cohort 1: Placebo	Drug: Placebo; Intravenous, Placebo control for blinding, Normal Saline, Single dose
Experimental: Cohort 1: 900 mg linezolid	Drug: Linezolid 900 mg; Intravenous, 900 mg linezolid, single dose; Other Names: Zyvox
Experimental: Cohort 1: 1200 mg linezolid	Drug: Linezolid 1200 mg; Intravenous, 1200 mg linezolid, single dose; Other Names: Zyvox
Placebo Comparator: Cohort 2: Placebo	Drug: Placebo; Intravenous, Placebo control for blinding, Normal Saline, Single dose
Experimental: Cohort 2: 600 mg linezolid	Drug: Linezolid 600 mg; Intravenous, 600 mg linezolid, single dose; Other Names: Zyvox
Experimental: Cohort 2: 1200 mg linezolid	Drug: Linezolid 1200 mg; Intravenous, 1200 mg linezolid, single dose; Other Names: Zyvox
Active Comparator: Cohort 2: 400 mg Moxifloxacin	Drug: Moxifloxacin 400 mg; Oral, 400 mg moxifloxacin, single dose; Other Names: Avelox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)	All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.	From the time the subject had taken at least one dose of study treatment up to 5 weeks
Cohort 2: Mean Time-Matched Difference in Time Corresponding to Beginning of Depolarization to Repolarization of the Ventricles, Corrected for Heart Rate Using Fridericia's Formula (QTcF Interval) Between Linezolid 600 mg and 1200 mg Compared to Placebo	The time corresponding to the beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for ventricular rate (VR) using the QT and VR from each electrocardiogram by Fridericia's formula (QTcF = QT divided by cube root of VR in seconds). A measure of dispersion is not available.	0.5, 1, 2, 4, 8, 12, 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Inf) and Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC Last)	AUC inf = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. AUC last = Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).	predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion
Cohort 1: Maximum Observed Plasma Concentration (Cmax)		predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion
Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2)	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion
Cohort 1: Clearance of Linezolid (CL)	Drug clearance = Dose / AUC inf	predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion
Cohort 1: Steady-State Volume of Distribution (Vss)	Vss = (mean residence time [The average total time molecules of a given dose spend in the body] extrapolated to infinity) multiplied by CL	predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion
Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo	A measure of dispersion is not available.	0.5, 1, 2, 4, 8, 12, 24 hours post-dose
Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo	A measure of dispersion is not available.	0.5, 1, 2, 4, 8, 12, 24 hours post-dose
Cohort 2: AUC Inf and AUC Last	AUC inf = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. AUC last = Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).	Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Cohort 2: Cmax		Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Cohort 2: Tmax and t1/2	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Tmax is the time to reach Cmax.	Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Cohort 2: CL	Drug clearance = Dose / AUC inf	Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Cohort 2: Vss	Vss = (mean residence time [The average total time molecules of a given dose spend in the body] extrapolated to infinity) multiplied by CL	Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Cohort 2: Number of Subjects With AEs and SAEs	All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.	From the time the subject had taken at least one dose of study treatment up to 5 weeks

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: November 20, 2008
• First Submitted That Met QC Criteria: November 20, 2008
• First Posted (Estimate): November 21, 2008

Study Record Updates

• Last Update Posted (Estimate): June 22, 2010
• Last Update Submitted That Met QC Criteria: May 17, 2010
• Last Verified: May 1, 2010

More Information

Terms related to this study

• Keywords: Linezolid, QTc interval, pharmacokinetics, therapeutic dose, supra-therapeutic dose
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Linezolid; Moxifloxacin
• Other Study ID Numbers: A5951151