András Varró
Department of Pharmacology and PharmacotherapyUniversity of Szeged, Hungary
Albert Szent-Györgyi Medical Center2007
The importantance of cardiac repolarization reserve in safety pharmacology
Clinical significance of drug induced QT-prolongation and related syndromes: an update
Developmental costWithdrawal cost:
~ 800 million USD~ 500 - ? million USD
Withdrawn drugs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
Due to Torsades de pointes:
Torsades de pointes
RARE: with terfenadine 1/50000
„If you remember, I did mention possible side-effects.”
„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)
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
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 %
– Concomittant ion-channel modifier
– Undetected ion channel polymorphisms or mutation( LQT)
Moxifloxacin (fluroquinolone) as positive control 6 – 10 ms QT prolongation
E. Kevin Heist et al. Heart Rhythm 2005;2:S1–S8
Current clinical view of drug induced torsade pointes arrhythmia
QT lengtheningImportant antiarrhythmic mechanism
Sign of dangereous side effect of various drugs
Gaborit et al. J Physiol 582.2 (2007) pp 675–693
Regional differences
regular heart beat regular heart beat
1
3
4
6
7
ERP
ERP
ERP
ERP
ERP
ERP
5
extrasystole extrasystole
2
CONTROL100 nM L-735,821
50 m
V
200 ms
0 mV
CONTROL10 µM CHROMANOL 293B
0 mV
PURKINJE FIBER VENTRICULAR MUSCLE
The effect of IKs block on the APD in dog right ventricular muscleand Purkinje fiber
50 m
V
200 ms
0 mV
0 mV
Varro et al. J Physiol. 2000;523:67-81.
Experimental demonstration of the repolarization reserve
0 20 40 60 80 100 120 140
420
400
380
360
340
320
300
280
260
240
220
TIME (min)
AP
D (
ms
)
+ 100 nM L-735,821
100 ms
50 m
V
0 mV+ 100 nM L-735,821
E-4031 + VERATRINE
CONTROL
20
18
16
14
12
10
8
6
4
20
AP
D C
HA
NG
E (
%)
1 µM E-4031 + 1 µg/ml VERATRINE
n=7*
n=8
*
The effect of IKs block in pharmacologically lengthened APDin dog right ventricular muscle
Varro et al. J Physiol. 2000;523:67-81.
Experimental demonstration of the repolarization reserve
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.
Bilicki et al. Br J Pharmacol 2002; 137: 361-368
50
mV
200 ms
0 mV
CL = 5000 ms
IKs
0 mV
50 m
V200 ms
IKr
IKr+ IKs
0 mV
50 m
V
200 ms
CL = 5000 ms
IK1
200 ms
50
mV
0 mV
IKr
IKr+ IK1200 ms
50 m
V
0 mVEAD
Multiple K+ channel block and repolarization reserve
Chromanol 293B
Dofetilide + Chromanol 293B
BaCl2
Dofetilide + BaCl2
Repolarization Reserve
200 ms
Ik1
CURRENT
INCX
IKr(H)ERG+miRP1
IKsKvLQT1+minK
Kir 2.1 (Kir2.x)
Ito
Kv4.3+Kv1.4KChIP2
CHANNEL PROTEIN
ICaCav1.2+Cav21
NCX
INaNav1.5+Nav1
Kääb et al. 2003; Eur Heart Journal
Sotalol test
The role of repolarization reserve in patients
Ibutilide test
Kilborn et al. Circulation 2000. 102: II-673
Change in QTc (msec)
Nu
mb
er
of
Su
bje
cts
The role of repolarization reserve in patients
Ibutilide test
Decreased repolarization reserve due to ventricular electrophysiological remodelling
Pharmacogenetics (LQT syndrome, ion-channel polymorphysm etc.)
Gender
Ischaemia
Renal failure
Diabetes
Drugs
Heart failure
0.0
0.1
0.2
0.3
0.4
0.5
0 1 2 3
Cu
mu
lati
ve m
ort
alit
y
Years
QTc < 454ms
QTc > 454ms
QTc < 454ms
QTc > 454ms
QTc Interval as Guide to Select Those Patients With Congestive Heart Failure …Brendorp et al. Circulation 2001; 103:1422-1427
Placebo-treated patients
Dofetilide-treated patients
DIAMOND-CHF Trial and repolarization reserve
Rodriguez et al. JAMA 2001, Vol 285:1322-1326
Repolarization reserve and gender
Liu et al. Circulation. 2005;112:3239-3246.
Cisapride rescues misprocessed mutant (LQT3) sodium channel trafficing
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?
temporalbeat-to-beat
spatialPurkinje fiber, M-cell, Subendocardial,
Subepicardial,Basal, Apex
How to measure?
2
2
10 /
/log
mv
mvvi HRHR
QTQTQT
2301
nn DD
STV
Varriability index
Short-term beat-to-beat varriability
Brennan et al. IEEE, 2001; 48:1342-47
QT or APD
Berger et al., Circulation, 1997
Poincaré plot
120 140 160 180 200 220 240120
140
160
180
200
220
240
QT
inte
rval
(D
n+1
; m
s) QT interval (D
n; ms)
Thomsen et al, Circulation. 2004; 110:2453-2459.
Different effects of sotalol and amiodarone – two drugs lengthening QT – on the short term
repolarization variability
Combined IKr plus IKs block in the ventricular myocyte:beat-to-beat variability of repolarization
Volders et al. Circulation. 2003;107:2753-2760
TdP –
TdP +
Control
Dofetilide (0.025 mg/kg)
Dofetilide (0.025 mg/kg) +HMR-1556 (1 mg/kg)
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
QT
-in
terv
al n
(s)
0
0.2
0.3
0.4
0.5
Dog 1
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
Dog 2
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
Dog 3
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
Dog 4
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
Dog 5
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
QT
-in
terv
al n
(s)
0
0.2
0.3
0.4
0.5
Dog 6
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
Dog 7
0 0.2 0.3 0.4 0.5QT-interval n-1 (s)
Dog 8
Effects of IKr-blocker dofetilide and IKs-blocker HMR-1556
on QT-interval variability in conscious dogs
Lengyel et al. Br J of Pharmacol 2007; advance online publication
*
0
50
100
150
200
250
300
350
400
450
500
*
0
1
2
3
4
5
6
7
Controls (n = 11)Heart failure patients (n = 11)
QT QTc QT-STV
ms
ms
0
10
20
30
40
50
60
QT QTc QT-STV
Pe
rce
nta
ge
ch
an
ge
(%
)
Changes in cardiac repolarization in patients with heart failure
*
0
1
2
3
4
5
QT QTc QT-STV
ms
ms
Controls (n = 41)Psychiatric patients (n = 54)
*
0
50
100
150
200
250
300
350
400
450
500
-5
0
5
10
15
20
25
30
35
QT QTc QT-STV
Pe
rce
nta
ge
ch
an
ge
(%
)
Changes in cardiac repolarization in patients treated with antipsychotic drugs
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 electro-physiological 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 repola-rization 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.”
REPOLARIZATION
RESERVE
