Mechanistic Evaluation of the Effects of Ranolazine on Ventricular Repolarization

1
Mechanistic Evaluation of the Effects of
Ranolazine on Ventricular Repolarization

• Luiz Belardinelli, MD
• VP, Drug Research andPharmacological Sciences
• CV Therapeutics, Inc.

2
QT Prolongation Alone Does Not Predict Torsade de
Pointes (TdP)
80
60
40
Incidence of TdP,
Almokalant
Dofetilide
d-Sotalol
20
Amiodarone
0
55
55
70
75
Increase in QTc Interval, msec
A better surrogate of pro-arrhythmic potential is
needed.
Canine chronic AV node block modelVos MA, et al.
Circulation. 1998981125-1135.
3
Drug-Induced Torsade de Pointes Relationship to
EADs and Dispersion
Repolarizing current
?
1
?
Action Potential Duration (APD)
Early afterdepolarizations
? Dispersion of repolarization
Substrate
Trigger
Torsade de Pointes
4
3
EADs ? Ectopic Beats Extrasystoles
5
Transmural Differences of Ventricular
RepolarizationA Mechanism for Arrhythmias
4
APD, msec
LV chamber
Normal
230
Epicardium
LV wall
289
Mid-myocardium
271
Endocardium
Arrhythmias enabled
Shimizu et al. JCE. 199910154-164.
6
The Effects of Ranolazine On
1
Ion currents Ventricular AP (and QT)
EADs Dispersion of ventricular repolarization
2
3
4

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

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

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Ion Current EffectsIKr and Late INa
1
Ion current Effect on action potential Effect on ECG Ranolazine potency IC50
IKr inhibition Lengthens ? QT 12 µM
Late INa inhibition Shortens ? QT 5 µM
Late INa effect mitigates IKr effect
Average therapeutic concentration range 850 to
2500 ng/mL (2 to 6 µM)
8
Ranolazine Prolongs APD and QT Interval but This
Effect Is Not Heart Rate Dependent
2
A. Isolated hearts
80
E-4031 (1 µM)
Slope 0.055
60
?APD90, msec
40
Slope 0.003
20
Ranolazine (5 µM)
0
150
100
75
60
Pacing rate, b/min
Okada et al. J Am Coll Cardiol. 19962784-89.
MARISA (CVT 3031).
9
Ranolazine Does Not Induce Early
Afterdepolarizations (EADs)
3

• IKr blockers (d-sotalol, E-4031) - LQT2
• IKs blocker (chromanol 293B) - LQT1
• Late INa enhancer (anemone toxin, ATX-II) - LQT3

Ranolazine reverses APD (and QT) prolongation,
suppresses EADs and ventricular tachycardia (VT)
caused by
X
X
X
Ectopicbeats
?
?
EADs
torsade
With 3 nM ATX.
10
Suppression by Ranolazine of d-Sotalol-Induced
EAD in Purkinje Fiber Preparation
Ranolazine suppresses EADs induced by quinidine,
anenome toxin (ATX II), E-4031
11
Ranolazine Suppresses Ectopic Beats, EADs, and VT
Induced by IKr Block in Female Rabbit Hearts
CT-11
A. Control
12
Ranolazine Suppresses Ectopic Beats, EADs, and VT
Induced by IKr Block in Female Rabbit Hearts
CT-12
A. Control
13
Ranolazine Does Not Increase Transmural
Dispersion of Repolarization (TDR)
4
Canine LV wedge. BCL 2000 msec.
14
EADs and Increased Dispersion of Ventricular
Repolarization Predicts the Occurrence of TdP in
Humans
Drug evaluated Drug action in canine LV myocardium Drug action in canine LV myocardium TdP reported in humans
Drug evaluated Induces EADs Increases TDR TdP reported in humans
Quinidine ( 5 µM)
d-Sotalol
Terfenadine
Erythromycin
Cisapride
Sodium pentobarbital
Ranolazine
?IKr ? ?APD and QT
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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