# Presentation: 716295

## ECG Studies Assessing Alfuzosin HCl Cardiac Repolarization Potential

- Alfuzosin: alpha-1 blocker for benign prostatic hyperplasia
- developed by
- Sanofi-Synthelabo Research

## Focus

- 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.

## Alfuzosin QT Increase is Not Clinically 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.

## Alfuzosin Presentation

**Background**: Jon Villaume, PhD, Sanofi-Synthelabo
**Pharmacokinetics**: Jim Oppermann, PhD, Sanofi-Synthelabo
**ECG studies**: Wocjiech Zareba, MD, PhD, University of Rochester
**Conclusions**: Jeremy Ruskin, MD, Massachusetts General Hospital

## External Consultants

- Pierre Maison-Blanche, MD, Hôpital Lariboisiere, Paris
- Craig Pratt, MD, Methodist Hospital
- Claus Roehrborn, MD, University of Texas
- Joel Verter, PhD, Statistics Collaborative

## Alfuzosin Marketing History

- First approved in 1987 for benign prostatic hyperplasia (BPH)
- Currently approved in all of Europe, Canada and Australia

## Clinical 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

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

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

**Drug**

## NDA Cardiac Repolarization Assessment

- 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

## NDA Approvable Letter Issues

- “The QTc interval must be measured using an FDA agreed upon validated methodology.”
- Study assessing interaction with maximum ketoconazole dose lacking

## Response to Approvable Letter 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

## Alfuzosin Pharmacokinetic Profile

- Jim Oppermann, PhDSenior Vice President Drug Safety EvaluationSanofi-Synthelabo Research

## Outline

- 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

## Factors Impacting Single Dose vs. 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

## Time 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)

## Factors Impacting Single Dose vs. 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

## Comparison of Exposure After Single and Multiple Administration

- Mean ± SD

## Comparison of Exposure after Single and Multiple Administration

- Mean ± SD

## Comparison of Exposure After Single and Multiple Administration

| Dose: 10 mg | Cmax
(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 and Multiple Administration**

- Exposure after repeated administration is similar to single dose

## Factors Impacting Single Dose vs. 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

## 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****               **

## Accumulation of Metabolites

- 14C 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

- Mean ± SD

## Single Dose Design for Alfuzosin QT Evaluation is Appropriate

## The 40 mg Dose in the QT Interval Studies Provides Exposure Exceeding That Achieved in the Clinical Situation

## Factors that Increase Exposure 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

## Alfuzosin Interaction with Ketoconazole Study 5056

- With ketoconazole 400 mg
-  Cmax  x 2.3 :  AUC X 3

- Time (hours)

- 0

- 1

- 2

- 4

- 6

- 8

- 10

- 14

- 24

- 48

- Alfuzosin concentration (ng/mL)

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- LOQ

- Alfuzosin alone

- Alfuzosin + ketoconazole

- Mean ± SD

## Factors that Increase Exposure to Alfuzosin

- Alfuzosin: Special Populations/Interaction

- Fold-increase

- 0

- 1

- 2

- 3

- 4

- 5

- Repeateddosevs.singledose

- With Ketoconazole 400 mg

- Moderate

- Severe

- Hepatic impairment

- Renal impairment

- Age > 75yrs

- C

- max

- AUC

- With Diltiazem

- Dose 40 mg

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

- C**max** achieved after 40 mg single dose exceeds peak levels in Phase III studies

- 10 mg Alfuzosin

- 40 mg Alfuzosin

- Day 28     Day 56     Day 84                Study 5105

- N=72

- N=83

- N=56

- Mean ± SD

## Predicted Cmax and AUC at Steady State in Various Populations Co-treated with Ketoconazole vs. 40 mg Single Dose

## Conclusion

- 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

## Alfuzosin ECG Trials Methods and Results

- Wojciech Zareba, MD, PhDAssociate Professor of CardiologyUniversity of Rochester,Rochester, NY

## Alfuzosin ECG TrialsOverview

- Heart rate increase and impact on QT interval assessment
- Holter Bin Method
- Study designs
- Results

## Heart Rate Changes with 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

## Methods for QT Interval 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)

## QT Correction for Changing Heart Rate

| 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 Rate**

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

- 24 ms over-correction

## Alfuzosin ECG Trials

- Heart Rate increase and impact on QT interval assessment
- Holter Bin Method
- Study designs
- Results

## Slide 37

## Holter 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

## Holter Bin MethodIndividual QT/RR Relationship

- 320

- 340

- 360

- 380

- 400

- 420

- 440

- 460

- 700

- 800

- 900

- 1000

- 1100

- 1200

- 1300

- QT (msec)

- Placebo

- QT = Ai*RRBi

- RR (msec)

## Alfuzosin ECG Trials

- Heart Rate increase and impact on QT interval assessment
- Holter Bin Method
- Study designs
- Results

## Alfuzosin 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

## Study 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

## Study 4532 – ResultsHolter 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 |

## Study 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

## Design 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

## Study 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)

## Holter Bin Method Time Window

**Holter Bin Method Time Window**

- Time (hours)

- 0

- 2

- 4

- 5

- 6

- 7

- 8

- 9

- 10

- 11

- 12

- 16

- 20

- 24

- Alfuzosin concentration (ng/mL)

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 40

- 45

- 50

- Moxifloxacin concentration (ng/mL)

- 0

- 500

- 1000

- 1500

- 2000

- 2500

- 3000

- 3500

- Alfuzosin 10 mg

- Alfuzosin 40 mg

- Moxifloxacin 400 mg

- Holter Period

## Power 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

## Alfuzosin ECG Trials

- Heart rate increase and impact on QT interval assessment
- Holter Bin Method
- Study designs
- Results

## Moxifloxacin Results

|  | Endpoint | Difference 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 |
| Traditional | QTcF | +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% |

## Alfuzosin 10 mg Results

|  | Endpoint | Difference 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 |
| Traditional | QTcF | +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% |

## Alfuzosin 40 mg Results

|  | Endpoint | Difference 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 |
| Traditional | QTcF | +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% |

## Holter Endpoints

-  QT (msec)

- Mean difference vs. placebo

## QT Changes at Various RR Intervals

- RR (msec)

- QT (msec)

- 75             71              67              63             60             57              55             52              50

- HR (bpm)

## Study 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

## Delta QTcNi at the Highest Concentrations

**Delta QTcNi at the Highest Concentrations**

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

- 80
- 60
- 40
- 20
- 0
- -20
- -40
- _60
- -80

- Delta QTcNi (msec)

-      Placebo            Alfuzosin 10mg          Alfuzosin 40mg

- n= 1470
- Slope = 0.138
- Intercept = -5.971

- ...                   ...              ...

## Study 5105: Summary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: Summary****Assay Sensitivity**

## Study 5105: Summary

**Alfuzosin 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.

## Summary and Conclusions

- Jeremy Ruskin, M.D.Director, Cardiac Arrhythmia ServiceMassachussetts General Hospital

## Outline

- Limitations of Correction Formulae
- Adequacy of Study 5105 Study Design
- Results of ECG Studies
- Pharmacovigilance
- Safety Margin
- Conclusions

## Limitations 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 observations
- slope = -0.005 Int.= 395.10

- N=495 observations
- slope = -0.100 Int.= 492.32

- N=495 observations
- slope = -0.040 Int.= 430.59

- N=495 observations
- slope = -0.006 Int.= 396.17

- RR(msec)

- RR(msec)

- RR(msec)

- RR(msec)

- QTcB(msec)

- QTcN (msec)

- QTcNi (msec)

- QTcF (msec)

## Holter Bin Method

- Avoids need for heart rate correction
- Correlates closely with QTcNi
- Limited experience in drug trials

## Adequacy 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

## Fold Increase in Exposure

**Fold Increase in Exposure**

- Fold increase

## Study 5105 QT/QTc Results

**Study 5105 QT/QTc Results**

| Method | Alfuzosin 
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 |

## Changes in QT1000

- msec

## Outlier 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

## Post Marketing Experience

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

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

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

**Drug**

## Comparison of Therapeutic Concentrations and HERG IC50

- ng/ml

## Comparison of Therapeutic Concentrations and HERG IC50

- ng/ml

**Comparison of Therapeutic Concentrations and HERG IC****50**

## Terfenadine

**Terfenadine**

- Change in QTcB

- msec

- non-peak

## Conclusions: QT Interval Effects of Alfuzosin

- Well characterized
- Small (<5 msec) effect size
- Approximately half the effect of moxifloxacin
- No outliers
- No torsades de pointe