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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