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Clinical significance of drug induced QTprolongation and related syndromes: an update
The importantance of cardiac repolarization reserve in safety
pharmacology
András Varró
Department of Pharmacology and Pharmacotherapy
University of Szeged, Hungary
Albert Szent-Györgyi Medical Center
2007
Torsades de pointes
„QT interval prolongation, with the potential for fatal arrhythmias, has been the single most common cause of
withdrawal or relabeling of marketed drugs in the last decade” (Roden et al. J.Clin.Invest. 115:2025-2032; 2005)
RARE: with terfenadine 1/50000
Developmental cost
Withdrawal cost:
~ 800 million USD
~ 500 - ? million USD
Due to Torsades de pointes:
Withdrawn drugs
Terfenadine
Astemizole
Grepafloxacin
Cisapride
None approval or suspended development
several
Complicated approval
Moxifloxacin
Ziprasidone
Approved with QT cautions in labeling
numerous
Re-labeling
Thioridazine
Droperidol
„If you remember, I did mention possible side-effects.”
Drugs That Prolong the Q-T Interval and/or Induce Torsades de Pointes
www.Torsades.org
Raymond L. Woosley, MD, Ph.D.
Arizona CERT (Center for Education and Research on Therapeutics)
Information from the FDA-approved drug labeling and the medical literature.
Closed and last revised: 03/01/2006
Current clinical view of drug induced torsade pointes
arrhythmia
Primary drug effect (IKr IHERG blockade)
Secondary risk factors (effect amplifiers)
– High doses or rapid administration
– Metabolic inhibition
– Impaired elimination
– Bradycardia
– Hypokalemia ; hypomagnesemia
– Heart disease (CHF, LVF, diabetes)
– Female gender 70 %
E. Kevin Heist et al. Heart Rhythm 2005;2:S1–S8
– Concomittant ion-channel modifier
– Undetected ion channel polymorphisms or mutation( LQT)
Moxifloxacin (fluroquinolone) as positive control 6 – 10 ms QT prolongation
QT lengthening
Important antiarrhythmic mechanism
Sign of dangereous side effect of various drugs
Regional differences
Gaborit et al. J Physiol 582.2 (2007) pp 675–693
regular heart beat
regular heart beat
extrasystole
extrasystole
1
ERP
ERP
2
3
7
4
ERP
ERP
6
ERP
5
ERP
Experimental demonstration of the repolarization reserve
The effect of IKs block on the APD in dog right ventricular muscle
and Purkinje fiber
PURKINJE FIBER
VENTRICULAR MUSCLE
CONTROL
100 nM L-735,821
0 mV
50 mV
0 mV
200 ms
CONTROL
10 µM CHROMANOL 293B
0 mV
50 mV
0 mV
200 ms
Varro et al. J Physiol. 2000;523:67-81.
Experimental demonstration of the repolarization reserve
The effect of IKs block in pharmacologically lengthened APD
in dog right ventricular muscle
CONTROL
E-4031 + VERATRINE
+ 100 nM L-735,821
+ 100 nM L-735,821
0 mV
50 mV
1 µM E-4031 + 1 µg/ml VERATRINE
420
400
380

100 ms
340
320
300
280
260
240
220
0
20
40
60
80
100
120
140
APD CHANGE (%)
APD (ms)
360
TIME (min)
Varro et al. J Physiol. 2000;523:67-81.
20
18
16
14
12
10
8
6
4
2
0
n=8
*
*
n=7
Conclusion in 2000
Varro et al. J Physiol. 2000;523:67-81.
Role of IKs in the repolarization reserve in
the human ventricle
Jost et al., Circulation. 2005; 112:1393-1400.
Multiple K+ channel block and repolarization reserve
Dofetilide + Chromanol 293B
0 mV
50 mV
Chromanol 293B
IKs
CL = 5000 ms
IKr
0 mV
200 ms
EAD
50 mV
200 ms
IKr+ IKs
50 mV
0 mV
Dofetilide + BaCl2
0 mV
0 mV
IK1
CL = 5000 ms
200 ms
IKr
50 mV
50 mV
BaCl2
200 ms
IKr+ IK1
200 ms
Bilicki et al. Br J Pharmacol 2002; 137: 361-368
Repolarization Reserve
200 ms
CHANNEL PROTEIN
CURRENT
Nav1.5+Navb1
INa
Cav1.2+Cava2d1
ICa
Kv4.3+Kv1.4
KChIP2
Ito
(H)ERG+miRP1
IKr
KvLQT1+minK
IKs
Kir 2.1 (Kir2.x)
Ik1
NCX
INCX
The role of repolarization reserve in patients
Sotalol test
Kääb et al. 2003; Eur Heart Journal
The role of repolarization reserve in patients
Number of Subjects
Ibutilide test
Ibutilide test
Change in QTc (msec)
Kilborn et al. Circulation 2000. 102: II-673
Decreased repolarization reserve due to ventricular
electrophysiological remodelling
 Pharmacogenetics (LQT syndrome,
ion-channel polymorphysm etc.)
 Gender
 Ischaemia
 Renal failure
 Diabetes
 Drugs
 Heart failure
DIAMOND-CHF Trial and repolarization reserve
Placebo-treated patients
Cumulative mortality
Dofetilide-treated patients
QTc < 454ms
0.5
QTc > 454ms
QTc > 454ms
0.4
0.3
0.2
QTc < 454ms
0.1
0.0
0
1
2
3
Years
QTc Interval as Guide to Select Those Patients With Congestive Heart Failure …
Brendorp et al. Circulation 2001; 103:1422-1427
Repolarization reserve and gender
Rodriguez et al. JAMA 2001, Vol 285:1322-1326
Cisapride rescues misprocessed mutant (LQT3) sodium
channel trafficing
Liu et al. Circulation. 2005;112:3239-3246.
How to predict torsades de pointes
arrhythmia ?
HERG assay ?
Action potential duration in dog Pf ?
QTc ?
QT dispersion ?
APD triangularization (SCREENIT system – Hondeghem) ?
QT/APD short term variability ?
Variability of Repolarization
What does it mean?
spatial
temporal
Purkinje fiber, M-cell, Subendocardial,
Subepicardial,Basal, Apex
beat-to-beat
How to measure?
QT or APD
Varriability index
Berger et al., Circulation, 1997
Short-term beat-to-beat varriability
STV 
 Dn1  Dn
30  2
Brennan et al. IEEE, 2001; 48:1342-47
240
QT interval (Dn+1; ms)
 QTv / QTm2 
QTvi  log 10 
2 
 HRv / HRm 
Poincaré plot
220
200
180
160
140
120
120
140
160
180
200
QT interval (Dn; ms)
220
240
Different effects of sotalol and amiodarone –
two drugs lengthening QT – on the short term
repolarization variability
Thomsen et al, Circulation. 2004; 110:2453-2459.
Combined IKr plus IKs block in the ventricular myocyte:
beat-to-beat variability of repolarization
Volders et al. Circulation. 2003;107:2753-2760
Effects of IKr-blocker dofetilide and IKs-blocker HMR-1556
on QT-interval variability in conscious dogs
TdP +
Dog 1
QT-interval n (s)
0,5
0,4
0,3
0,2
Dog 2
Dog 3
Dog 4
Dog 5
0.5
0,5
0,5
0,5
0,5
0.4
0,4
0,4
0,4
0,4
0.3
0,3
0,3
0,3
0,3
0.2
0,2
0,2
0,2
0,2
0
0
0,1
0.2
0.3
0.4
QT-interval n-1 (s)
0
0.5
0
0,1
0.2
0.3
0.4
QT-interval n-1 (s)
0,1
0,1
0,2
0,3
0,4
0.2
0.3
0.4
QT-interval n-1 (s)
0
0
0
0
0.5
0 0,5
0,1
0,2
0,3
0.5
0
0.2
0.3
0.4
QT-interval n-1 (s)
0
0
0,4
0,1
0,1
0,5
0,2
0,3
0,4
0,1
0.5
0
0.2
0.3
0.4
QT-interval n-1 (s)
0.5
0
0 0,5
0,1
0,2
0,3
0,4
0 0,5
0,1
0,2
0,3
0,4
0,5
TdP –
Dog 7
Dog 6
QT-interval n (s)
0,5
0,4
0,3
0,2
Dog 8
0.5
0,5
0.4
0,4
0.3
0,3
0,3
0.2
0,2
0,2
Control
0,5
Dofetilide (0.025 mg/kg)
0,4
Dofetilide (0.025 mg/kg) +
HMR-1556 (1 mg/kg)
0
0
0,1
0.2
0.3
0.4
QT-interval n-1 (s)
0
0
0.5
0,1
0.2
0.3
0.4
QT-interval n-1 (s)
0,1
0,2
0,3
0,4
0
0.2
0
0
0
0.5
0,1
0
0,5
0,1
0,2
0,3
0,4
0,5 0
0,1
0,2
0.3
0.4
QT-interval n-1 (s)
0.5
Lengyel et al. Br J of Pharmacol 2007; advance online publication
0,3
0,4
0,5
Changes in cardiac repolarization in
patients with heart failure
Changes in cardiac repolarization in
patients treated with antipsychotic drugs
Controls (n = 11)
Heart failure patients (n =711)
500
450
*
6
500
*
*
400
5
250
4
3
200
150
300
ms
ms
300
4
350
ms
350
ms
5
*
450
400
250
200
2
2
100
1
50
0
QTc
1
50
0
0
0
QT
3
150
100
QT-STV
60
Percentage change (%)
Percentage change (%)
Controls (n = 41)
Psychiatric patients (n = 54)
50
40
30
20
10
QT
QTc
QT-STV
QT
QTc
QT-STV
35
30
25
20
15
10
5
0
0
QT
QTc
QT-STV
-5
Drug indrustry
Development of life saving drugs
(antiarrhythmics, cardiotonics, AIDS drugs etc.)
Endpoint: mortality
Development of quality of life
improving drugs
(pl. antihistamins, CNS and GI drugs etc.)
Endpoint: not mortality
„I guess we should have tried it on the
rats first.”
General conclusion
1.
We should first reach a concensus
what degree or any kind of
mortality can be tolerated.
2.
Before treatment we should assess
the susceptability of the patients
regarding possible QT lengthening
(repolarization reserve)
3.
In
the
future
during
drug
development, to design and
control
safety
pharmacology
studies deeper cardiac electrophysiological background and
further basic research is required.
”Are you coming hunting, or are you gonna
sit around here all day inventing?”
Specific conclusion considering the role of
repolarization reserve
1.
Cardiac muscle has strong safety
margin
of
repolarization
(„REPOLARIZATION RESERVE”).
Decrease of this repolarization
reserve does not necessarily lead
to marked change of repolarization
but
makes
hearts
susceptible to arrhythmias.
2.
Multiple K+ channel block can
result excessive repolarization
lengthening by eliminating the
repolarization
reserve
and
therefore it can associate with
increased proarrhythmic risk.
“Are you sure about this, Dave? It
seems odd that a pointy head and
long beak is what makes them fly.”