1

ECG Studies Assessing ECG Studies Assessing Alfuzosin HCl Cardiac Alfuzosin HCl Cardiac

Repolarization PotentialRepolarization Potential

Alfuzosin: alpha-1 blocker for benign prostatic hyperplasia

developed by

Sanofi-Synthelabo Research

2

FocusFocus• Studies employing a sensitive assay were

adequate to assess a cardiac repolarization effect.

• They detected a small alfuzosin QT increase of 2-3 msec at 4 times therapeutic dose.

• This small increase is not clinically significant as confirmed by substantial clinical experience.

3

Alfuzosin QT Increase is Not Alfuzosin QT Increase is Not Clinically SignificantClinically Significant

• This increase is the maximum likely to be produced.

• It is well below increase of an approved control known to produce a modest increase.

• Known problem drugs produce much higher increases.

• Surveillance of extensive market use produced no risk signal.

4

Alfuzosin PresentationAlfuzosin Presentation

• BackgroundBackground: Jon Villaume, PhD, Sanofi-Synthelabo

• PharmacokineticsPharmacokinetics: Jim Oppermann, PhD, Sanofi-Synthelabo

• ECG studiesECG studies: Wocjiech Zareba, MD, PhD, University of Rochester

• ConclusionsConclusions: Jeremy Ruskin, MD, Massachusetts General Hospital

5

External ConsultantsExternal Consultants

• Pierre Maison-Blanche, MD, Hôpital Lariboisiere, Paris

• Craig Pratt, MD, Methodist Hospital

• Claus Roehrborn, MD, University of Texas

• Joel Verter, PhD, Statistics Collaborative

6

Alfuzosin Marketing HistoryAlfuzosin Marketing History

• First approved in 1987 for benign prostatic hyperplasia (BPH)

• Currently approved in all of Europe, Canada and Australia

7

Clinical Study Results in NDAClinical Study Results in NDA

• Improvement in BPH symptoms and urinary flow rate

• Therapeutic dose: 10 mg once daily without titration

• Well tolerated with favorable safety profile

8

IC50 (µM) IC50/

therapeutic Cmax

Reference

Drugs

Astemizole

Cisapride

Terfenadine

0.003 ± 0.0003

0.049 ± 0.008

0.060 ± 0.009

0.49

0.59

10

1-Receptor

Antagonists

Doxazosin

Prazosin

Terazosin

Alfuzosin

Tamsulosin

2.5 ± 0.3

3.4 ± 0.4

21.4 ± 2.9

83.3 ± 16.6

104.8 ± 0.6

14-93

57

54-109

2400

2250-4366

Comparison of Inhibition of HERG Comparison of Inhibition of HERG Potassium Currents by Various DrugsPotassium Currents by Various Drugs

Drug

9

NDA Cardiac Repolarization NDA Cardiac Repolarization AssessmentAssessment

• No clinically significant QT effect using Holter Bin Method in Study 4532

• No ventricular arrhythmia signal and no report of torsades de pointe – From clinical studies or surveillance of

3.7 million patient years of marketed use

10

NDA Approvable Letter IssuesNDA Approvable Letter Issues

• “The QTc interval must be measured using an FDA agreed upon validated methodology.”

• Study assessing interaction with maximum ketoconazole dose lacking

11

Response to Approvable Response to Approvable Letter IssuesLetter Issues

• Plan– Study 5105: Compare single doses of

10 and 40 mg alfuzosin and moxifloxacin to placebo

– Study 5056 : Assess interaction with maximum dose of ketoconazole (400 mg)

• FDA agreement with plan obtained

12

Alfuzosin Alfuzosin Pharmacokinetic ProfilePharmacokinetic Profile

Jim Oppermann, PhDSenior Vice President Drug Safety Evaluation

Sanofi-Synthelabo Research

13

OutlineOutline

• QT interval evaluation after single dose is appropriate

• The 40 mg dose in the QT interval studies provided exposure exceeding that achieved in the clinical situation

14

Factors Impacting Single Dose Factors Impacting Single Dose vs. Multiple Dose ECG Designsvs. Multiple Dose ECG Designs

• Time to reach steady state for alfuzosin

• Exposure after single administration vs. exposures after repeated administration

• Accumulation of metabolites after repeated administration

15

Time to Reach Steady State - AlfuzosinTime to Reach Steady State - Alfuzosin

Steady state is reached after a single dose

Individual and mean (SD) trough levels observed over 5 days of repeated administration (10 mg OD)

Day

1 2 3 4 5 6 7

Alfu

zosi

n pl

asm

a co

ncen

trat

ion

(ng/

mL)

0

1

2

3

4

5

6

7

8

First dose

16

Factors Impacting Single Dose Factors Impacting Single Dose vs. Multiple Dose ECG Designsvs. Multiple Dose ECG Designs

• Time to reach steady state for Alfuzosin

• Exposure after single administration vs. exposures after repeated administration

• Accumulation of metabolites after repeated administration

17

Comparison of Exposure After Comparison of Exposure After Single and Multiple AdministrationSingle and Multiple Administration

Time (h)

0 4 8 12 16 20 24

Alfu

zosi

n p

lasm

a c

on

cent

ratio

n (

ng/m

L)

0

4

8

12

16

20 Alfuzosin 10 mg OD after a single dose (N=58)

Mean ± SD

18

Comparison of Exposure after Comparison of Exposure after Single and Multiple AdministrationSingle and Multiple Administration

Time (h)

0 4 8 12 16 20 24

Alfu

zosi

n pl

asm

a co

ncen

trat

ion

(ng/

mL)

0

4

8

12

16

20Alfuzosin 10 mg OD after repeated dose, at steady-state (N=42)Alfuzosin 10 mg OD after a single dose (N=58)

Mean ± SD

19

Dose: 10 mgCmax

(ng/mL)Mean (S.D.)

AUC0-24

(ng.h/mL)Mean (S.D.)

Ctrough

(ng/mL)Mean (S.D.)

Single dose (N=58) 13.5 (6.8) 172 (79) 3.5 (2.0)

Repeated dose (N=42) 13.6 (5.6) 194 (75) 3.2 (1.6)

Ratio Estimate

Repeated vs single dose

[90% CI]

1.03

[0.88-1.19]

1.15

[1.00-1.32]

0.97

[0.80-1.17]

Comparison of Exposure After Single Comparison of Exposure After Single and Multiple Administrationand Multiple Administration

• Exposure after repeated administration is similar to single dose

20

Factors Impacting Single Dose Factors Impacting Single Dose vs. Multiple Dose ECG Designsvs. Multiple Dose ECG Designs

• Time to reach steady state for Alfuzosin

• Exposure after single administration vs. exposures after repeated administration

• Accumulation of metabolites after repeated administration

21

Accumulation of Metabolites Accumulation of Metabolites

Profile of plasma 14C 1 hour after oral administration of 14C-alfuzosin in man

• Alfuzosin is the major circulating compound.• Major metabolites are glucuronide conjugates.

Glucuronides of Alfuzosin&

O-Desmethyl Alfuzosin

Alfuzosin

0.0 min 50.0 min

22

Accumulation of MetabolitesAccumulation of Metabolites14C and alfuzosin plasma concentrations after administration of

14C-alfuzosin (10 mg) to three human subjects

• Metabolites rapidly formed and eliminated with similar half-life as alfuzosin• No accumulation of metabolites expected

0

20

40

60

80

100

0 2 4 6 8 10

Time (hours)

ng/m

L

Equiv. of Alfuzosin

Alfuzosin

Mean ± SD

23

Single Dose Design for Single Dose Design for Alfuzosin QT Evaluation Alfuzosin QT Evaluation

is Appropriateis Appropriate

24

The 40 mg Dose in the QT Interval The 40 mg Dose in the QT Interval Studies Provides Exposure Studies Provides Exposure

Exceeding That Achieved in the Exceeding That Achieved in the Clinical SituationClinical Situation

25

Factors that Increase Factors that Increase Exposure to AlfuzosinExposure to Alfuzosin

• Alfuzosin elimination primarily by metabolism through CYP3A4

• Interaction with ketoconazole Study 5056 • 12 healthy male volunteers• Alfuzosin 10 mg single alone or plus

ketoconazole (at Day 7 of the keto treatment period)

• Ketoconazole 400 mg for 8 days

26

Alfuzosin Interaction with Alfuzosin Interaction with Ketoconazole Study 5056Ketoconazole Study 5056

With ketoconazole 400 mg Cmax x 2.3 : AUC X 3

Time (hours)01 2 4 6 8 10 14 24 48

Alfu

zosi

n co

ncen

trat

ion

(ng/

mL)

0

5

10

15

20

25

30

35

LOQ

Alfuzosin alone

Alfuzosin + ketoconazole

Mean ± SD

27

Factors that Increase Factors that Increase Exposure to AlfuzosinExposure to Alfuzosin

Alfuzosin: Special Populations/Interaction

Fo

ld-i

ncre

ase

0

1

2

3

4

5

Repeateddosevs.

singledose

With Ketoconazole 400 mg

Moderate Severe

Hepatic impairment

Renal impairmentAge > 75yrs

Cmax AUC

With Diltiazem

Dose 40 mg

28

Comparison of Exposure at 40 mg Single Comparison of Exposure at 40 mg Single Dose and Peak (10-14 hours) Plasma Dose and Peak (10-14 hours) Plasma

Concentration in PatientsConcentration in Patients

Cmax achieved after 40 mg single dose exceeds peak levels in Phase III studies

Day 28 Day 56 Day 84 PDY5105, 40 mg

Alfu

zo

sin

Pla

sm

a C

on

ce

ntr

atio

n (

ng

/mL

)

0

20

40

60

80

10 mg Alfuzosin

40 mg Alfuzosin

Day 28 Day 56 Day 84 Study 5105

N=72 N=83 N=56

Mean ± SD

29

Predicted CPredicted Cmax max and AUC at Steady State in and AUC at Steady State in

Various Populations Co-treated with Various Populations Co-treated with Ketoconazole vs. 40 mg Single DoseKetoconazole vs. 40 mg Single Dose

30

ConclusionConclusion• QT interval evaluation after single dose

is appropriate: – Steady state is reached on Day 1– Exposure after repeated administration

is similar to single dose– Metabolites are formed rapidly and

have a similar half-life as alfuzosin (formation rate limited)

• The 40 mg dose in the QT interval studies provides exposure exceeding that achieved in the clinical situation

31

Alfuzosin ECG TrialsAlfuzosin ECG Trials Methods and ResultsMethods and Results

Wojciech Zareba, MD, PhDAssociate Professor of Cardiology

University of Rochester,Rochester, NY

32

Alfuzosin ECG TrialsAlfuzosin ECG TrialsOverviewOverview

• Heart rate increase and impact on QT interval assessment

• Holter Bin Method

• Study designs

• Results

33

Heart Rate Changes Heart Rate Changes with Alfuzosinwith Alfuzosin

Alfuzosin

10 mg

Alfuzosin

40 mg

Moxifloxacin 400 mg

HR (bpm)

Mean*1.5 3.7 1.5

Subjects

with HR

>15 bpm

7% 33% 9%

*HR differences vs. placebo – Study 5105

34

Methods for QT Methods for QT Interval CorrectionInterval Correction

Traditional QT correction formulae

Bazett QTcB (QTcB = QT/RR1/2)

Fridericia QTcF (QTcF = QT/RR1/3)

Study-population based

QTcN: regression modeling (QTcN = QT/RRB)

Individual subject-specific

QTcNi: regression modeling (QTcNi = QT/RRBi)

35

Heart Rate

QT(msec)

QTcB (msec)

QTcF (msec)

QTcNi(msec)

60 (bpm) 380 380 380 380

65 (bpm) 370 385 380 377

75 (bpm) 360 404 388 380

QT Correction for Changing Heart RateQT Correction for Changing Heart Rate

Typical subject in study 5105 (QTcNi=QT/RR0.24 )

24 ms over-correction

36

Alfuzosin ECG TrialsAlfuzosin ECG Trials

• Heart Rate increase and impact on QT interval assessment

• Holter Bin Method

• Study designs

• Results

37

2. Classification of ECG complexes into 10 ms groups « Bins »

1000 msec RR Bin 1010 msec RR Bin

3. Averaging of complexes and measurement of QT intervals

QT1000QT1010

1. RR interval measurement

995 msec 1005 msec 1000 msec1007 msec995 msec 1005 msec1006 msec

38

Holter Bin MethodHolter Bin Method• Controls rather than corrects for heart rate

• Wide range of RR interval explored for each subject allowing:

– Direct comparison of absolute QT at the same HR between placebo and drug (non parametric)

– Development of QT / RR regression model

39

Holter Bin MethodHolter Bin MethodIndividual QT/RR RelationshipIndividual QT/RR Relationship

320

340

360

380

400

420

440

460

700 800 900 1000 1100 1200 1300

QT

(m

sec)

Placebo

QT = Ai*RRBi

Drug

QT800QT1000

QT1200

RR (msec)

40

Alfuzosin ECG TrialsAlfuzosin ECG Trials

• Heart Rate increase and impact on QT interval assessment

• Holter Bin Method

• Study designs

• Results

41

Alfuzosin ECG TrialsAlfuzosin ECG Trials

• Study 4532: included in original NDA

• Study 5105: comparison of single doses of 10 and 40 mg alfuzosin and 400 mg moxifloxacin to placebo

42

Study 4532Study 4532• Single-center, randomized, double-

blind, 4-way crossover study• 24 healthy male volunteers• Alfuzosin 10, 20, and 40 mg

and placebo• The study included Holter

recordings at:– Screening– 4 periods of single-dose administration

43

Study 4532 – ResultsStudy 4532 – ResultsHolter Bin Method

Treatment

QT1000 change from placebo

(msec)

95% CI p

Alfuzosin

10 mg+2.0 0.5 ; 3.4 0.011

Alfuzosin

20 mg+1.9 -0.1; 4.0 0.066

Alfuzosin

40 mg+1.7 -0.1 ; 3.5 0.059

44

Study 5105: ObjectivesStudy 5105: Objectives

• To validate the Holter Bin Method by using both a positive control and QT corrections from 12-lead ECG recordings

• To re-assess the effect of alfuzosin on QT interval using the Holter Bin Method

45

Design of Study 5105Design of Study 5105• Single-center, randomized, double-dummy,

4-way crossover study• 45 subjects• Alfuzosin 10 and 40 mg, placebo, and

moxifloxacin 400 mg (positive control)• Each period consisted of:

– A run-in placebo– Followed by a single-dose administration– Washout of 5 to 9 days between

successive periods 

46

Study EndpointsStudy Endpoints Primary (Holter Bin Method):

– Change in QT1000

– Change in QT at RR bin with the largestnumber of complexes

– Change in QT averaged over all RR bins

Secondary (Standard 12-lead ECGs)– Individual based correction QTcNi– Population based correction QTcN– Traditional formulae QTcF, QTcB

Exploratory (Holter Bin Method)– QT at any fixed RR bin (QT800, …, QT1200)

47

Holter Bin Method Time WindowHolter Bin Method Time Window

Time (hours)

0 2 4 5 6 7 8 9 101112 16 20 24

Alfuzo

sin c

once

ntr

ati

on (

ng/m

L)

0

5

10

15

20

25

30

35

40

45

50

Moxifl

oxacin

conce

ntra

tion

(ng/m

L)

0

500

1000

1500

2000

2500

3000

3500

Alfuzosin 10 mg

Alfuzosin 40 mg

Moxifloxacin 400 mg

Holter Period

48

Power ConsiderationsPower Considerations

• More than 80% power to detect a moxifloxacin QTcB as small as 5 msec (to confirm assay sensitivity)

• Needs N=45 subjects

• Provides more than 80% power to detect a 3 msec QT1000 for any of the treatment groups

49

Alfuzosin ECG TrialsAlfuzosin ECG Trials

• Heart rate increase and impact on QT interval assessment

• Holter Bin Method

• Study designs

• Results

50

Moxifloxacin ResultsMoxifloxacin Results

EndpointDifference vs. placebo

(msec)

95% CI p

Holter QT1000 +7.0 4.4 ; 9.6 0.0001

Individual QTcNi +9.4 6.9 ; 11.8 0.0001

Population QTcN +9.4 6.9 ; 11.9 0.0001

TraditionalQTcF +10.3 7.7 ; 13.0 0.0001

QTcB +11.9 8.3 ; 15.6 0.0001

Heart Rate HR 1.5 bpm

>15 bpm 9%

51

Alfuzosin 10 mg ResultsAlfuzosin 10 mg Results

EndpointDifference vs. placebo

(msec)95% CI p

Holter QT1000 +0.1 -2.5 ; 2.6 0.97

Individual QTcNi +0.5 -2.0 ; 2.9 0.70

Population QTcN +0.5 -2.0 ; 3.0 0.71

TraditionalQTcF +1.6 -1.1 ; 4.3 0.24

QTcB + 3.3 -0.3 ; 6.9 0.07

Heart Rate HR 1.5 bpm

>15 bpm 7%

52

Alfuzosin 40 mg ResultsAlfuzosin 40 mg Results

EndpointDifference vs. placebo

(msec)95% CI p

Holter QT1000 +2.9 0.3 ; 5.5 0.03

Individual QTcNi +4.7 2.2 ; 7.1 0.0003

Population QTcN +4.6 2.1 ; 7.0 0.0004

TraditionalQTcF +6.9 4.2 ; 9.5 0.0001

QTcB + 10.8 7.2 ; 14.4 0.0001

Heart Rate HR 3.7 bpm

>15 bpm 33%

53

Holter EndpointsHolter Endpoints

QT

(m

sec)

0

2

4

6

8

10

QT1000 QT change at largestsample size RR bin

QT change averaged overall RR bins

Alfuzosin 10 mg Alfuzosin 40 mg Moxifloxacin

Mean difference vs. placebo

54

QT Changes at VariousQT Changes at Various RR Intervals RR Intervals

-4

-2

0

2

4

6

8

10

12

800 850 900 950 1000 1050 1100 1150 1200

Alfuzosin 10 mg Alfuzosin 40 mg Moxifloxacin

RR (msec)

QT

(m

sec)

75 71 67 63 60 57 55 52 50HR (bpm)

55

Study 5105 – ECG OutliersStudy 5105 – ECG Outliers• No subject with QTcF, QTcN or QTcNi >450

msec or change >60 msec • 7 subjects with QTcB >450 msec

– 2 placebo, 1 alfuzosin 10 mg, 3 alfuzosin 40 mg, 1 moxifloxacin

– maximum 458 msec

• 4 subjects with QTcB >60 msec– 1 alfuzosin 10 mg, 3 alfuzosin 40 mg

• Alfuzosin outlier values are associated with a substantial HR increase vs. baseline

56

Delta QTcNi at the Highest ConcentrationsDelta QTcNi at the Highest Concentrations

SubjConc

(ng/mL)D HR (bpm)

QTcNi (msec) D QTcNi

39 109.0 21 392 5114 106.0 7 389 039 98.1 4 381 -6

114 90.6 5 380 -9114 87.8 0 391 2114 85.6 2 390 139 83.8 20 386 -1

114 81.7 -1 381 -831 80.5 8 410 2539 75.9 18 391 431 74.6 0 388 331 74.5 -2 390 529 74.3 8 424 2429 72.8 3 425 2532 71.6 9 391 -534 71.0 10 412 12

0 10 20 30 40 50 60 70 80 90 100 110 Concentration (ng/mL)

80

60

40

20

0

-20

-40

_60

-80

Delt

a Q

TcN

i (m

sec)

Placebo Alfuzosin 10mg Alfuzosin 40mg

n= 1470Slope = 0.138

Intercept = -5.971

… … ...

57

• Study 5105 using Holter Bin approach had the required assay sensitivity.

• With therapeutic dose of moxifloxacin 400 mg:

• Holter Bin Method documented a 7 msec increase in QT1000.

• QTc correction methods resulted in 9-12 msec increase.

Study 5105: SummaryStudy 5105: SummaryAssay SensitivityAssay Sensitivity

58

Study 5105: SummaryStudy 5105: SummaryAlfuzosin ResultsAlfuzosin Results

• At therapeutic dose of 10 mg, alfuzosin did not produce significant changes in QT1000.

• At 4 times the therapeutic dose, alfuzosin produced a mean QT1000 change of 2.9 msec, less than half what is observed with moxifloxacin administered at therapeutic dose.

• Whatever the dose, no clinically relevant QT/QTc changes were observed.

59

Summary and ConclusionsSummary and Conclusions

Jeremy Ruskin, M.D.Director, Cardiac Arrhythmia Service

Massachussetts General Hospital

60

OutlineOutline

• Limitations of Correction Formulae

• Adequacy of Study 5105 Study Design

• Results of ECG Studies

• Pharmacovigilance

• Safety Margin

• Conclusions

61

Limitations of Correction FormulaeLimitations of Correction Formulae

500 700 900 1100 1300 1500 1700

500

450

400

350

300

500 700 900 1100 1300 1500 1700

500

450

400

350

300

500 700 900 1100 1300 1500 1700

500

450

400

350

300

500 700 900 1100 1300 1500 1700

500

450

400

350

300

N=495 observationsslope = -0.005 Int.= 395.10

N=495 observationsslope = -0.100 Int.= 492.32

N=495 observationsslope = -0.040 Int.= 430.59

N=495 observationsslope = -0.006 Int.= 396.17

RR(msec) RR(msec)

RR(msec)RR(msec)

QTcB(msec)

QTcN (msec)

QTcNi (msec)

QTcF (msec)

62

Holter Bin MethodHolter Bin Method

• Avoids need for heart rate correction

• Correlates closely with QTcNi

• Limited experience in drug trials

63

Adequacy of Study DesignAdequacy of Study Design

• Four-fold dose range

• Exposures exceeded those seen with maximum metabolic inhibition or in patients with renal impairment

• Moxifloxacin control for assay sensitivity

• Internal validation of Holter Bin Method

64

Fold Increase in ExposureFold Increase in Exposure

0

1

2

3

4

5

Cmax AUC

Alfuzosin 10 mg + DiltiazemAlfuzosin 10 mg + Ketoconazole 400 mgAlfuzosin 40 mg

Fold

in

crease

65

Study 5105 QT/QTc ResultsStudy 5105 QT/QTc Results

MethodAlfuzosin

10 mg (msec)

Alfuzosin

40 mg (msec)Moxifloxacin

400 mg (msec)

QT1000 Holter Bin

0.1 2.9 7.0

QTcNi 0.5 4.7 9.4

QTcN 0.5 4.6 9.4

66

Changes in QTChanges in QT10001000 

0

2

4

6

8

10

Alfuzosin 10 mg Alfuzosin 20 mg Alfuzosin 40 mg

Study 4532

Study 5105

mse

c

67

Outlier AnalysisOutlier Analysis

• No outliers (QTc >450 msec or QTc >60 msec) with any correction method except Bazett

• All QTcB outliers occurred in association with significant increases in HR

• No outliers (QTc >500 msec) in any study with any method

• No QT/QTc greater than 440 msec by any correction method in subjects with concentrations > 5x therapeutic

68

Post Marketing ExperiencePost Marketing Experience

• No report of torsades de pointe in over 1.35 billion estimated therapy days (estimated 3.7 million patient years)

69

IC50 (µM) IC50/

therapeutic Cmax

Reference

Drugs

Astemizole

Cisapride

Terfenadine

0.003 ± 0.0003

0.049 ± 0.008

0.060 ± 0.009

0.49

0.59

10

1-Receptor

Antagonists

Doxazosin

Prazosin

Terazosin

Alfuzosin

Tamsulosin

2.5 ± 0.3

3.4 ± 0.4

21.4 ± 2.9

83.3 ± 16.6

104.8 ± 0.6

14-93

57

54-109

2400

2250-4366

Comparison of Inhibition of HERG Comparison of Inhibition of HERG Potassium Currents by Various DrugsPotassium Currents by Various Drugs

Drug

70

Comparison of Therapeutic Comparison of Therapeutic Concentrations and HERG ICConcentrations and HERG IC5050

ng/m

l

0

5000

10000

15000

20000

25000

30000

35000

Alfuzozin HERGIC50

Alfuzosin 10mg Alfuzosin + keto Renalimpairment

Alfuzosin 40mg Age Alfu +keto+renalimpair

71

1

10

100

1000

10000

100000

Alfuzozin HERGIC50

Alfuzosin 10mg Alfuzosin + keto Renalimpairment

Alfuzosin 40mg Age Alfu +keto+renalimpair

ng/m

lComparison of Therapeutic Comparison of Therapeutic

Concentrations and HERG ICConcentrations and HERG IC5050

72

0

10

20

30

40

50

60

70

80

90

Terfenadine Terfenadine +Ketoconazole

TerfenadineTerfenadineChange in QTcB

mse

cnon-peak

73

Conclusions: QT Interval Conclusions: QT Interval Effects of Effects of AlfuzosinAlfuzosin

• Well characterized

• Small (<5 msec) effect size

• Approximately half the effect of moxifloxacin

• No outliers

• No torsades de pointe