andrás varró department of pharmacology and pharmacotherapy university of szeged, hungary

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Withdrawn drugs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