András Varró Department of Pharmacology and Pharmacotherapy University of Szeged, Hungary

1. Clinical significance of drug induced QT-prolongation and related syndromes: an update The importantance of cardiac repolarization reserve in safety pharmacology András Varró Department of Pharmacology and PharmacotherapyUniversity of Szeged, Hungary Albert Szent-Györgyi Medical Center 2007

4. Developmental cost Withdrawal cost: ~ 800 million USD ~ 500 - ? million USD 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 J.Clin.Invest. 115:2025-2032; 2005) RARE: with terfenadine 1/50000 Due to Torsades de pointes: • Withdrawn drugsTerfenadineAstemizoleGrepafloxacinCisapride • None approval or suspended developmentseveral • Complicated approvalMoxifloxacinZiprasidone • Approved with QT cautions in labelingnumerous • Re-labelingThioridazineDroperidol „If you remember, I did mention possible side-effects.”

5. Drugs That Prolong the Q-T Interval and/or Induce Torsades de Pointeswww.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.

6. Closed and last revised: 03/01/2006

7. 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 % • Concomittant ion-channel modifier • Undetected ion channel polymorphisms or mutation( LQT) E. Kevin Heist et al. Heart Rhythm 2005;2:S1–S8 Moxifloxacin (fluroquinolone) as positive control 6 – 10 ms QT prolongation

8. QT lengthening Important antiarrhythmic mechanism Sign of dangereous side effect of various drugs

9. Regional differences Gaborit et al. J Physiol 582.2 (2007) pp 675–693

10. extrasystole extrasystole 1 ERP ERP 3 2 7 4 ERP ERP 6 5 ERP ERP regular heart beat regular heart beat

12. 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 0 mV 50 mV 200 ms CONTROL 10 µM CHROMANOL 293B 0 mV 0 mV 50 mV 200 ms Varro et al. J Physiol. 2000;523:67-81.

13. Experimental demonstration of the repolarization reserve n=8 * 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 1 µM E-4031 + 1 µg/ml VERATRINE 420 50 mV 400 380 360 100 ms  340 20 320 APD (ms) 18 300 16 14 280 12 APD CHANGE (%) 260 10 8 240 * 6 n=7 220 4 140 0 20 40 60 80 100 120 2 TIME (min) 0 Varro et al. J Physiol. 2000;523:67-81.

14. Conclusion in 2000 Varro et al. J Physiol. 2000;523:67-81.

15. Role of IKs in the repolarization reserve in the human ventricle Jost et al., Circulation. 2005; 112:1393-1400.

16. IKr+ IKs IKr 200 ms EAD 0 mV 0 mV 0 mV IKr+ IK1 IK1 IKr 50 mV 50 mV 50 mV CL= 5000 ms 200 ms 200 ms 200 ms Multiple K+ channel block and repolarization reserve Dofetilide + Chromanol 293B 0 mV 0 mV Chromanol 293B 50 mV IKs 50 mV CL = 5000 ms 200 ms Dofetilide + BaCl2 BaCl2 Bilicki et al. Br J Pharmacol 2002; 137: 361-368

17. Repolarization Reserve

18. Kv4.3+Kv1.4 KChIP2 Ito IKr (H)ERG+miRP1 KvLQT1+minK IKs 200 ms CHANNEL PROTEIN CURRENT Nav1.5+Navb1 INa ICa Cav1.2+Cava2d1 Ik1 Kir 2.1 (Kir2.x) NCX INCX

19. The role of repolarization reserve in patients Sotalol test Kääb et al. 2003; Eur Heart Journal

20. The role of repolarization reserve in patients Ibutilide test Ibutilide test Number of Subjects Change in QTc (msec) Kilborn et al. Circulation 2000. 102: II-673

21. Decreased repolarization reserve due to ventricular electrophysiological remodelling • Pharmacogenetics (LQT syndrome, ion-channel polymorphysm etc.) • Gender • Ischaemia • Renal failure • Diabetes • Drugs • Heart failure

22. DIAMOND-CHF Trial and repolarization reserve Placebo-treated patients Dofetilide-treated patients QTc < 454ms QTc > 454ms QTc > 454ms QTc < 454ms 0.5 0.4 0.3 Cumulative mortality 0.2 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

23. Repolarization reserve and gender Rodriguez et al. JAMA 2001, Vol 285:1322-1326

24. Cisapride rescues misprocessed mutant (LQT3) sodium channel trafficing Liu et al. Circulation. 2005;112:3239-3246.

25. 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 ?

26. Variability of Repolarization What does it mean? temporal beat-to-beat spatial Purkinje fiber, M-cell, Subendocardial, Subepicardial,Basal, Apex

27. How to measure? QT or APD Varriability index Poincaré plot Berger et al., Circulation, 1997 Short-term beat-to-beat varriability Brennan et al. IEEE, 2001; 48:1342-47

28. Different effects of sotalol and amiodarone – two drugs lengthening QT – on the short term repolarization variability Thomsen et al, Circulation. 2004; 110:2453-2459.

29. Combined IKr plus IKs block in the ventricular myocyte: beat-to-beat variability of repolarization Volders et al. Circulation. 2003;107:2753-2760

30. 0.5 QT-interval n (s) 0.4 0.3 0.2 0 0 0 0 0 0 0 0.2 0.2 0.2 0.2 0.2 0.2 0.3 0.3 0.3 0.3 0.3 0.3 0.4 0.4 0.4 0.4 0.4 0.4 0.5 0.5 0.5 0.5 0.5 0.5 Control QT-interval n-1 (s) QT-interval n-1 (s) QT-interval n-1 (s) QT-interval n-1 (s) QT-interval n-1 (s) QT-interval n-1 (s) Dofetilide (0.025 mg/kg) Dofetilide (0.025 mg/kg) + HMR-1556 (1 mg/kg) Dog 7 Dog 6 Dog 8 0.5 0.4 QT-interval n (s) 0.3 0.2 0 0.2 0.3 0.4 0.5 0 QT-interval n-1 (s) QT-interval n-1 (s) 0 0.2 0.3 0.4 0.5 Effects of IKr-blocker dofetilide and IKs-blocker HMR-1556 on QT-interval variability in conscious dogs TdP + Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 TdP – Lengyel et al. Br J of Pharmacol 2007; advance online publication

31. Controls (n = 41) Psychiatric patients (n = 54) 7 500 500 Controls (n = 11) Heart failure patients (n = 11) 5 * * 450 * 450 * 6 400 400 4 5 350 350 300 300 ms ms ms ms 4 3 250 250 3 200 200 2 150 150 2 100 100 1 1 50 50 0 0 0 0 QT QTc QT-STV QT QTc QT-STV 60 35 30 50 25 40 20 Percentage change (%) Percentage change (%) 30 15 20 10 10 5 0 0 QT QTc QT-STV QT QTc QT-STV -5 Changes in cardiac repolarization in patients with heart failure Changes in cardiac repolarization in patients treated with antipsychotic drugs

32. 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.”

33. General conclusion • We should first reach a concensus what degree or any kind of mortality can be tolerated. • Before treatment we should assess the susceptability of the patients regarding possible QT lengthening (repolarization reserve) • 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?”

34. Specific conclusion considering the role of repolarization reserve • 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. • Multiple K+ channel block can result excessive repolarization lengthening by eliminating the repolarization reserve and therefore it can associate with increased proarrhythmic risk. REPOLARIZATION RESERVE “Are you sure about this, Dave? It seems odd that a pointy head and long beak is what makes them fly.”