Bacterial Infections
Conditions
Keywords
Linezolid, QTc interval, pharmacokinetics, therapeutic dose, supra-therapeutic dose
Brief summary
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.
Interventions
DRUGPlacebo
Intravenous, Placebo control for blinding, Normal Saline, Single dose
DRUGLinezolid 900 mg
Intravenous, 900 mg linezolid, single dose
DRUGLinezolid 1200 mg
Intravenous, 1200 mg linezolid, single dose
DRUGLinezolid 600 mg
Intravenous, 600 mg linezolid, single dose
DRUGMoxifloxacin 400 mg
Oral, 400 mg moxifloxacin, single dose
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the time the subject had taken at least one dose of study treatment up to 5 weeks | All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported. |
| 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 | 0.5, 1, 2, 4, 8, 12, 24 hours post-dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2) | 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 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Cohort 1: Clearance of Linezolid (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 | Drug clearance = Dose / AUC inf |
| Cohort 1: Steady-State Volume of Distribution (Vss) | 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 | Vss = (mean residence time \[The average total time molecules of a given dose spend in the body\] extrapolated to infinity) multiplied by CL |
| Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 0.5, 1, 2, 4, 8, 12, 24 hours post-dose | A measure of dispersion is not available. |
| Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 0.5, 1, 2, 4, 8, 12, 24 hours post-dose | A measure of dispersion is not available. |
| 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) | 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 | 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). |
| Cohort 2: AUC Inf and AUC Last | Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose | 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). |
| Cohort 2: Cmax | Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose | — |
| Cohort 2: Tmax and t1/2 | Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Tmax is the time to reach Cmax. |
| Cohort 2: CL | Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose | Drug clearance = Dose / AUC inf |
| Cohort 2: Vss | Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose | Vss = (mean residence time \[The average total time molecules of a given dose spend in the body\] extrapolated to infinity) multiplied by CL |
| Cohort 2: Number of Subjects With AEs and SAEs | From the time the subject had taken at least one dose of study treatment up to 5 weeks | All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported. |
| 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 | — |
Countries
Singapore
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Placebo, Linezolid 900 mg and 1200 mg Subjects were randomly assigned to placebo followed by linezolid 900 mg then 1200 mg linezolid in Sequence 1; or, linezolid 900 mg then linezolid 1200 mg followed by placebo in Sequence 2; or, linezolid 900 mg then placebo followed by linezolid 1200 mg in Sequence 3. There was a washout period of 48 hours between doses. | 9 |
| Cohort 2: Placebo, Linezolid 600 mg and 1200 mg, Moxifloxacin Subjects were randomly assigned to placebo first then moxifloxacin followed by linezolid 600 mg and 1200 mg linezolid last in Sequence 1; or linezolid 600 mg first then linezolid 1200 mg followed by placebo and moxifloxacin last in Sequence 2; or, linezolid 1200 mg first then moxifloxacin 400 mg followed by linezolid 600 mg and placebo last in Sequence 3; or, moxifloxacin 400 mg first then placebo followed by linezolid 1200 mg and 600 mg linezolid last in Sequence 4. There was a washout period of 48 hours between each dose. | 40 |
| Total | 49 |
Baseline characteristics
| Characteristic | Cohort 1: Placebo, Linezolid 900 mg and 1200 mg | Cohort 2: Placebo, Linezolid 600 mg and 1200 mg, Moxifloxacin | Total |
|---|---|---|---|
| Age, Customized 18 - 44 years | 8 participants | 36 participants | 44 participants |
| Age, Customized <18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized 45 - 64 years | 1 participants | 4 participants | 5 participants |
| Age, Customized >=65 years | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 4 Participants | 20 Participants | 24 Participants |
| Sex: Female, Male Male | 5 Participants | 20 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 9 | 3 / 9 | 2 / 9 | 4 / 40 | 3 / 40 | 7 / 40 | 10 / 40 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 40 | 0 / 40 | 0 / 40 | 0 / 40 |
Outcome results
Primary
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.
Time frame: From the time the subject had taken at least one dose of study treatment up to 5 weeks
Population: Safety Analysis Set (SAS): All subjects who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 participants |
| Cohort 1: Placebo | Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Cohort 1: 900 mg Linezolid | Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 participants |
| Cohort 1: 900 mg Linezolid | Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Cohort 1: 1200 mg Linezolid | Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| Cohort 1: 1200 mg Linezolid | Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
Primary
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.
Time frame: 0.5, 1, 2, 4, 8, 12, 24 hours post-dose
Population: The pharmacokinetic (PK) parameter analysis population was defined as all subjects randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Placebo | 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 | 1 hour | 419.71 milliseconds (msec) |
| Cohort 1: Placebo | 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 | 8 hours | 409.75 milliseconds (msec) |
| Cohort 1: Placebo | 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 | 4 hours | 418.85 milliseconds (msec) |
| Cohort 1: Placebo | 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 | 0.5 hour | 421.31 milliseconds (msec) |
| Cohort 1: Placebo | 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 | 24 hours | 414.83 milliseconds (msec) |
| Cohort 1: Placebo | 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 | 12 hours | 412.99 milliseconds (msec) |
| Cohort 1: Placebo | 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 | 2 hours | 414.27 milliseconds (msec) |
| Cohort 1: 900 mg Linezolid | 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 | 4 hours | 421.92 milliseconds (msec) |
| Cohort 1: 900 mg Linezolid | 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 | 0.5 hour | 422.34 milliseconds (msec) |
| Cohort 1: 900 mg Linezolid | 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 | 1 hour | 420.89 milliseconds (msec) |
| Cohort 1: 900 mg Linezolid | 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 | 2 hours | 412.30 milliseconds (msec) |
| Cohort 1: 900 mg Linezolid | 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 | 8 hours | 412.25 milliseconds (msec) |
| Cohort 1: 900 mg Linezolid | 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 | 12 hours | 413.45 milliseconds (msec) |
| Cohort 1: 900 mg Linezolid | 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 | 24 hours | 417.27 milliseconds (msec) |
| Cohort 1: 1200 mg Linezolid | 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 | 8 hours | 411.13 milliseconds (msec) |
| Cohort 1: 1200 mg Linezolid | 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 | 1 hour | 422.67 milliseconds (msec) |
| Cohort 1: 1200 mg Linezolid | 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 | 24 hours | 415.47 milliseconds (msec) |
| Cohort 1: 1200 mg Linezolid | 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 | 12 hours | 411.98 milliseconds (msec) |
| Cohort 1: 1200 mg Linezolid | 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 | 4 hours | 418.45 milliseconds (msec) |
| Cohort 1: 1200 mg Linezolid | 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 | 2 hours | 419.80 milliseconds (msec) |
| Cohort 1: 1200 mg Linezolid | 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 | 0.5 hour | 419.84 milliseconds (msec) |
Comparison: Inferential analysis at 0.5 hour post-dose90% CI: [-0.7, 3.64]
Comparison: Inferential analysis at 1 hour post-dose90% CI: [-5.13, -0.79]
Comparison: Inferential analysis at 2 hour post-dose90% CI: [-7.7, -3.36]
Comparison: Inferential analysis at 4 hour post-dose90% CI: [-1.77, 2.57]
Comparison: Inferential analysis at 8 hour post-dose90% CI: [-3.54, 0.8]
Comparison: Inferential analysis at 12 hour post-dose90% CI: [-1.16, 3.18]
Comparison: Inferential analysis at 24 hour post-dose90% CI: [-2.81, 1.53]
Comparison: Inferential analysis at 0.5 hour post-dose90% CI: [0.32, 4.66]
Comparison: Inferential analysis at 1 hour post-dose90% CI: [-3.95, 0.39]
Comparison: Inferential analysis at 2 hour post-dose90% CI: [-9.68, -5.34]
Comparison: Inferential analysis at 4 hour post-dose90% CI: [1.3, 5.64]
Comparison: Inferential analysis at 8 hour post-dose90% CI: [-1.04, 3.3]
Comparison: Inferential analysis at 12 hour post-dose90% CI: [-0.7, 3.64]
Comparison: Inferential analysis at 24 hour post-dose90% CI: [-0.37, 3.97]
Secondary
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).
Time frame: 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
Population: PK parameter analysis population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Placebo | 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 | 223.49 microgram (ug)*hours (hr)/mL | Standard Deviation 47.372 |
| Cohort 1: Placebo | 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 last | 211.26 microgram (ug)*hours (hr)/mL | Standard Deviation 48.542 |
| Cohort 1: 900 mg Linezolid | 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 last | 332.26 microgram (ug)*hours (hr)/mL | Standard Deviation 71.313 |
| Cohort 1: 900 mg Linezolid | 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 | 346.89 microgram (ug)*hours (hr)/mL | Standard Deviation 77.867 |
Secondary
Cohort 1: Clearance of Linezolid (CL)
Drug clearance = Dose / AUC inf
Time frame: 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
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 1: Clearance of Linezolid (CL) | 1.0173 mL/minute (min)/kilogram (kg) | Standard Deviation 0.14637 |
| Cohort 1: 900 mg Linezolid | Cohort 1: Clearance of Linezolid (CL) | 0.8813 mL/minute (min)/kilogram (kg) | Standard Deviation 0.16623 |
Secondary
Cohort 1: Maximum Observed Plasma Concentration (Cmax)
Time frame: 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
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 1: Maximum Observed Plasma Concentration (Cmax) | 22.3 ug/mL | Standard Deviation 3.681 |
| Cohort 1: 900 mg Linezolid | Cohort 1: Maximum Observed Plasma Concentration (Cmax) | 29.37 ug/mL | Standard Deviation 6.08 |
Secondary
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
Time frame: 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
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 1: Steady-State Volume of Distribution (Vss) | 0.6016 L/kg | Standard Deviation 0.06869 |
| Cohort 1: 900 mg Linezolid | Cohort 1: Steady-State Volume of Distribution (Vss) | 0.5776 L/kg | Standard Deviation 0.04605 |
Secondary
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.
Time frame: 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
Population: PK parameter analysis population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2) | Tmax | 1.0 hr |
| Cohort 1: Placebo | Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2) | t1/2 | 6.9 hr |
| Cohort 1: 900 mg Linezolid | Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2) | Tmax | 1.0 hr |
| Cohort 1: 900 mg Linezolid | Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2) | t1/2 | 7.1 hr |
Secondary
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).
Time frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Population: PK parameter analysis population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: AUC Inf and AUC Last | AUC Inf | 141.75 ug *hr/mL | Standard Deviation 36.156 |
| Cohort 1: Placebo | Cohort 2: AUC Inf and AUC Last | AUC Last | 129.52 ug *hr/mL | Standard Deviation 32.121 |
| Cohort 1: 900 mg Linezolid | Cohort 2: AUC Inf and AUC Last | AUC Inf | 328.75 ug *hr/mL | Standard Deviation 79.198 |
| Cohort 1: 900 mg Linezolid | Cohort 2: AUC Inf and AUC Last | AUC Last | 299.40 ug *hr/mL | Standard Deviation 62.096 |
Secondary
Cohort 2: CL
Drug clearance = Dose / AUC inf
Time frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: CL | 1.2825 mL/min/kg | Standard Deviation 0.36529 |
| Cohort 1: 900 mg Linezolid | Cohort 2: CL | 1.1000 mL/min/kg | Standard Deviation 0.27875 |
Secondary
Cohort 2: Cmax
Time frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: Cmax | 15.06 ug/mL | Standard Deviation 2.616 |
| Cohort 1: 900 mg Linezolid | Cohort 2: Cmax | 30.76 ug/mL | Standard Deviation 4.395 |
Secondary
Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo
A measure of dispersion is not available.
Time frame: 0.5, 1, 2, 4, 8, 12, 24 hours post-dose
Population: PK parameter analysis population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 2 hours | 430.07 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 8 hours | 420.53 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 1 hour | 429.50 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 12 hours | 419.02 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 4 hours | 428.29 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 24 hours | 421.99 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 0.5 hour | 423.11 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 24 hours | 415.47 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 0.5 hour | 419.84 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 1 hour | 422.67 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 2 hours | 419.80 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 4 hours | 418.45 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 8 hours | 411.13 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo | 12 hours | 411.98 msec |
Comparison: Inferential analysis at 0.5 hour post-dose90% CI: [1.1, 5.44]
Comparison: Inferential analysis at 1 hour post-dose90% CI: [4.66, 9]
Comparison: Inferential analysis at 2 hour post-dose90% CI: [8.1, 12.44]
Comparison: Inferential analysis at 4 hour post-dose90% CI: [7.67, 12.01]
Comparison: Inferential analysis at 8 hour post-dose90% CI: [7.23, 11.58]
Comparison: Inferential analysis at 12 hour post-dose90% CI: [4.87, 9.22]
Comparison: Inferential analysis at 24 hour post-dose90% CI: [4.35, 8.69]
Secondary
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.
Time frame: 0.5, 1, 2, 4, 8, 12, 24 hours post-dose
Population: PK parameter analysis population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 1 hour | 422.25 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 8 hours | 405.30 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 4 hours | 420.58 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 0.5 hour | 424.08 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 24 hours | 416.38 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 12 hours | 398.85 msec |
| Cohort 1: Placebo | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 2 hours | 421.15 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 4 hours | 419.66 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 0.5 hour | 422.60 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 1 hour | 414.80 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 2 hours | 415.40 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 8 hours | 399.66 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 12 hours | 396.56 msec |
| Cohort 1: 900 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 24 hours | 415.80 msec |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 8 hours | 406.40 msec |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 1 hour | 410.06 msec |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 24 hours | 419.06 msec |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 12 hours | 398.96 msec |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 4 hours | 418.40 msec |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 2 hours | 406.76 msec |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo | 0.5 hour | 420.60 msec |
Comparison: Inferential analysis at 8 hour post-dose90% CI: [-9.69, -1.58]
Comparison: Inferential analysis at 0.5 hour post-dose90% CI: [-5.54, 2.57]
Comparison: Inferential analysis at 1 hour post-dose90% CI: [-11.51, -3.4]
Comparison: Inferential analysis at 2 hour post-dose90% CI: [-9.81, -1.7]
Comparison: Inferential analysis at 4 hour post-dose90% CI: [-4.97, 3.13]
Comparison: Inferential analysis at 12 hour post-dose90% CI: [-6.34, 1.77]
Comparison: Inferential analysis at 24 hour post-dose90% CI: [-4.64, 3.47]
Comparison: Inferential analysis at 0.5 hour post-dose90% CI: [-7.54, 0.57]
Comparison: Inferential analysis at 1 hour post-dose90% CI: [-16.24, -8.13]
Comparison: Inferential analysis at 2 hour post-dose90% CI: [-18.44, -10.33]
Comparison: Inferential analysis at 4 hour post-dose90% CI: [-6.24, 1.87]
Comparison: Inferential analysis at 8 hour post-dose90% CI: [-2.95, 5.15]
Comparison: Inferential analysis at 12 hour post-dose90% CI: [-3.94, 4.17]
Comparison: Inferential analysis at 24 hour post-dose90% CI: [-1.37, 6.73]
Secondary
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.
Time frame: From the time the subject had taken at least one dose of study treatment up to 5 weeks
Population: SAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: Number of Subjects With AEs and SAEs | AEs | 3 participants |
| Cohort 1: Placebo | Cohort 2: Number of Subjects With AEs and SAEs | SAEs | 0 participants |
| Cohort 1: 900 mg Linezolid | Cohort 2: Number of Subjects With AEs and SAEs | SAEs | 0 participants |
| Cohort 1: 900 mg Linezolid | Cohort 2: Number of Subjects With AEs and SAEs | AEs | 7 participants |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Number of Subjects With AEs and SAEs | AEs | 4 participants |
| Cohort 1: 1200 mg Linezolid | Cohort 2: Number of Subjects With AEs and SAEs | SAEs | 0 participants |
| Moxifloxacin 400 mg | Cohort 2: Number of Subjects With AEs and SAEs | AEs | 10 participants |
| Moxifloxacin 400 mg | Cohort 2: Number of Subjects With AEs and SAEs | SAEs | 0 participants |
Secondary
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.
Time frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Population: PK parameter analysis population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: Tmax and t1/2 | Tmax | 1.083 hr |
| Cohort 1: Placebo | Cohort 2: Tmax and t1/2 | t1/2 | 6.095 hr |
| Cohort 1: 900 mg Linezolid | Cohort 2: Tmax and t1/2 | Tmax | 1.1 hr |
| Cohort 1: 900 mg Linezolid | Cohort 2: Tmax and t1/2 | t1/2 | 6.796 hr |
Secondary
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
Time frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Cohort 2: Vss | 0.6418 L/kg | Standard Deviation 0.08353 |
| Cohort 1: 900 mg Linezolid | Cohort 2: Vss | 0.6185 L/kg | Standard Deviation 0.0656 |