CT-1

Mechanistic Evaluation of the Effects of Ranolazine on

Ventricular Repolarization

Luiz Belardinelli, MD

VP, Drug Research andPharmacological Sciences

CV Therapeutics, Inc.

CT-2

QT Prolongation Alone Does Not Predict Torsade de Pointes (TdP)

0

20

40

60

80

55 55 70 75Increase in QTc Interval, msec

Inci

den

ce

of

Td

P, %

A better surrogate of pro-arrhythmic potential is needed.

Canine chronic AV node block model—Vos MA, et al. Circulation. 1998;98:1125-1135.A

lmo

kala

nt

d-S

ota

lol

Do

feti

lide

Am

iod

aro

ne

CT-3

Repolarizing current

Action Potential Duration (APD)

Early afterdepolarizations

↑ Dispersion of repolarization

Torsade de Pointes

SubstrateTrigger

Drug-Induced Torsade de Pointes— Relationship to EADs and Dispersion

22 Long QT

33 44

(EADs)

11IKr

Long QT

EADs ↑ DISPERSION

Torsade de Pointes

CT-4

33 EADs Ectopic BeatsExtrasystoles

Initiating beats for torsade

EADs

APD ( QT)

EADsAP

Ectopic beatsEctopicbeats ECG

Inward current (eg. INa, ICa)

CT-5

IKr blocker†

261

325

359

†d-Sotalol (IKr blockers) 100 µM.

LV wallLV wall

Epicardium

Mid-myocardium

Endocardium

LV chamberLV chamber

Transmural Differences of Ventricular Repolarization—A Mechanism for Arrhythmias

Normal

44

APD, msec

Arrhythmias enabled

230

271

289

98

Shimizu et al. JCE. 1999;10:154-164.

Dispersion 59

CT-6

The Effects of Ranolazine On:

Ion currents

Ventricular AP (and QT)

EADs

Dispersion of ventricular repolarization

Models• Single myocytes• Cardiac tissue• Isolated hearts• Anesthetized dogs• Humans

Conditions (risk factors)• Bradycardia (pauses)• Electrolytes ( Ko, Mgo)• Gender (female)• “Ion channel mutations”• With Isoproterenol• Disease (eg, CHF, ischemia)

11

22

33

44

CT-7

Ion currentEffect on

action potentialEffect on

ECGRanolazine potency IC50

IKr inhibition Lengthens QT 12 µM

Late INa inhibition Shortens QT ≥ 5 µM

Average therapeutic concentration range850 to 2500 ng/mL (~2 to 6 µM)

Late ILate INaNa effect mitigates I effect mitigates IKr Kr effecteffect

Ion Current Effects—IKr and Late INa11

CT-8

Ranolazine Prolongs APD and QT Interval but This Effect Is Not Heart Rate Dependent22

↑AP

D90

, mse

c

150 100 75 600

20

40

60

80

Pacing rate, b/min

Ranolazine (5 µM)

E-4031 (1 µM)

Slope = 0.055

Slope = 0.003

†Okada et al. J Am Coll Cardiol. 1996;27:84-89. MARISA (CVT 3031).

A. Isolated hearts

E-4031 Dofetilide Ranolazine0.00

0.05

0.10

0.15

0.20

0.25

Ch

ang

e w

ith

dru

g,

slo

pe QT vs heart rate

B. Humans†

Dofetilide-like IKr blocker

CT-9

EADsEctopicbeats

torsade

Ranolazine Does Not Induce Early Afterdepolarizations (EADs)33

XX XXXX†With 3 nM ATX.

1. IKr blockers (d-sotalol, E-4031) - LQT2

2. IKs blocker (chromanol 293B†) - LQT1

3. Late INa enhancer (anemone toxin, ATX-II) - LQT3

Ranolazine reverses APD (and QT) prolongation, suppresses EADs and ventricular tachycardia (VT) caused by

CT-10

Ranolazine suppresses EADs induced by: quinidine, anenome toxin (ATX II), E-4031

Suppression by Ranolazine of d-Sotalol-Induced EAD in Purkinje Fiber Preparation

Control

d-Sotalol 50 µM

EAD

Ranolazine 5 µM

Ranolazine 10 µM

CT-11Ranolazine Suppresses Ectopic Beats, EADs, and VT Induced by IKr Block in Female Rabbit Hearts

=

B. Ranolazine (30 µM)

Multi-channel Blocker

=

A. Control3-secpause

CT-11

CT-12Ranolazine Suppresses Ectopic Beats, EADs, and VT Induced by IKr Block in Female Rabbit Hearts

C. E-4031 (60 nM)

=

IKr Blocker

D. E-4031 + Ranolazine

=

D. E-4031 + Ranolazine (5 µM)

=APDAPD APDAPD

=

A. Control3-secpause

CT-12

CT-13

d-Sotalol, 100 µM ATX-II, 20 nM

Ranolazine

ATX-II

d-Sotalol

Canine LV wedge.BCL = 2000 msec.

Ranolazine Does Not Increase Transmural Dispersion of Repolarization (TDR)44

Hypokalemia

Ranolazine, µM

2 mM [K]o3 mM [K]o

0255075

100125

0 1 5 10 50 100 0 1 5 10 50 100

NS NSTDR,msec

0

25

50

75

100

125

0 1 5 10 50 100

NSTDR,msec

4 mM [K]o

Ranolazine, µM

CT-14EADs and Increased Dispersion of Ventricular Repolarization Predicts the Occurrence of TdP in Humans

Drug evaluated

Drug action in canine LV myocardium

TdP reported in

humans

Induces EADs

Increases TDR

Quinidine (≤ 5 µM) ++ ++ ++d-Sotalol ++ ++ ++Terfenadine ++ ++ ++Erythromycin ++ ++ ++Cisapride ++ ++ ++Sodium pentobarbital –– –– ––Ranolazine –– ––

↓IK

r → ↑

AP

D a

nd

QT

CT-15

Summary

Drugs that cause torsade de pointes– Prolong APD/QT– Induce EADs– Augment the dispersion of repolarization present in

the normal heart

Ranolazine, 1 to 100 µM, prolongs APD & QT, but– Does not induce EADs – Does not increase dispersion of ventricular

repolarization– Suppresses the arrhythmic effects of a number of QT-

prolonging drugs– Would not be expected to cause torsade de pointes