A Study To Assess The Effect Of Linezolid On QTc Interval

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Bacterial Infections

Intervention / Treatment
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* Drug: Placebo
* Drug: Linezolid 900 mg
* Drug: Linezolid 1200 mg
* Drug: Placebo
* Drug: Linezolid 600 mg
* Drug: Linezolid 1200 mg
* Drug: Moxifloxacin 400 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Linezolid, QTc interval, pharmacokinetics, therapeutic dose, supra-therapeutic dose