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REPOLARIZATION RESERVE AND SAFETY
PHARMACOLOGY
András Varró
Department of Pharmacology and Pharmacotherapy
University of Szeged, Hungary
Albert Szent-Györgyi Medical Center
2005
Torsades de pointes
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Withdrawn drugs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.”
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
The demonstration of the arrhythmogenic effect of the
early afterdepolarization (EAD) in canine heart preparations
Control
Purkinje fibre
Ventricular muscle
electrical
stimulation
electrical
stimulation
Ventricular muscle
Purkinje fibre
electrical
stimulation
Varró and Lathrop, J Cardiovasc Pharmacol (1990) 16:557-67
The demonstration of the arrhythmogenic effect of the
repolarization inhomogeneity in canine heart preparations
F.G. Akar, G-X Yan, C. Antzelevitch, D.S. Rosenbaum, Circulation. 2002;105:1247-1253.
regular beat
regular beat
Extrasystole
DAD or EAD
Extrasystole
DAD or EAD
1
2
3
7
4
6
5
Repolarization reserve
Role of IKs in the repolarization reserve in
the dog ventricle
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
rabbit
dog
Control
RR = 357 ms
QT = 277 ms
QTc = 267 ms
0 mV
50 mV
+ BaCl2 (10 µM )
Eliprodil (1 µM )
Control
RR = 363 ms
QT = 313 ms
QTc = 302 ms
+ Eliprodil (1 µM)
200 ms
RR = 460 ms
QT = 377 ms
QTc = 349 ms
1 mV
TdP
1s
Lengyel et al; Br J Pharmacol 2004; 143: 152−158
Conclusion from our experiments
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.
Multiple K+ channel block may
result excessive repolarization
lengthening 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.”
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
Combined IKr plus IKs block in the ventricular myocyte:
beat-to-beat variability of repolarization
Circulation. 2003
Effect of IKr block (dofetilide) on the short term APD variability
in single isolated myocites obtained from dog after chronic
A-V block induced hypertrophy
Thomsen et al. Circulation 2004;110:2460-2466.
Effect of IKr block on the APD variability after
cardiac hypertrophy in dog
Morten B. Thomsen et al, Circulation. 2004;110:2453-2459.
Effects of IKr-block (dofetilide) and IKs-block (HMR-1556)
on QT-interval variability in conscious dog
Dog 3
0.5
0.4
0.3
Control
Dofetilide (0.025 mg/kg)
Dofetilide (0.025 mg/kg) +
HMR-1556 (1 mg/kg)
0.2
0
QT-interval n (s)
QT-interval n (s)
0.5
Dog 9
0.4
0.3
Control
HMR-1556 (1 mg/kg)
0.2
0
0
0.2
0.3
0.4
QT-interval n-1 (s)
0.5
0
0.2
0.3
0.4
QT-intervaln-1
n-1(s)
(s)
QT-interval
0.5
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
0 0,5
0,1
0,2
0,3
0,4
0 0,5
0,1
0,2
0,3
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
0.3
0.4
QT-interval n-1 (s)
0.5
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
0.5
0,5
0,4
0,5
Effect of IKr-blocker dofetilide and IKs-blocker HMR-1556
on QT-interval in conscious dog
Dog 3
Control
Dofetilide (0.025 mg/kg)
Dofetilide (0.025 mg/kg)
+
HMR-1556 (1 mg/kg)
RR: 537 ms
QT: 243 ms
QTc: 331 ms
RR: 618 ms
QT: 333 ms
QTc: 423 ms
RR: 663 ms
QT: 392 ms
QTc: 481 ms
Drug indrustry
Development if 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 required.