Drug-Induced QT Interval Prolongation and Torsades de Pointes

1. Drug-Induced QT Interval Prolongation andTorsades de Pointes

3. Drug-Induced Torsades de Pointes • Low frequency event • Potentially life threatening • Not highly predictable despite known risk factors

4. QT Prolongation & Torsades de Pointes • Cardiac electrophysiology • Clinical pharmacology • Genetics • Regulatory medicine • Clinical Practice

5. QT Prolongation & Torsades de Pointes • Mechanisms of QT prolongation and TdP • Drug effects on the QT interval • Specific drugs associated with TdP • Risk factors for drug-induced TdP • Clinical and regulatory implications

6. Kathryn E. Williams: SWR-May 16: update closer to AC date and add ‘version’ date to slide A n t i c o n v u l s a n t s F o s p h e n y t o i n ; F e l b a m a t e A n t i h i s t a m i n e s A z e l a s t i n e ; C l e m a s t i n e A n t i - I n f e c t i v e s A m a n t a d i n e ; C l a r i t h r o m y c i n ; C h l o r o q u i n e ; F o s c a r n e t ; E r y t h r o m y c i n ; H a l o f a n t r i n e ; M e f l o q u i n e ; M o x i f l o x a c i n ; P e n t a m i d i n e ; S p a r f l o x a c i n ; Q u i n i n e ; T r i m e t h o p r i m - S u l f a m e t h o x a z o l e , K e t o c o n a z o l e A n t i n e o p l a s t i c s T a m o x i f e n C a r d i o v a s c u l a r : A n t i a r r h y t h m i c s A m i o d a r o n e ; B r e t y l i u m ; D i s o p y r a m i d e ; F l e c a i n i d e ; I b u t i l i d e ; P r o c a i n a m i d e ; Q u i n i d i n e ; S o t a l o l ; D o f e t i l i d e C a l c i u m C h a n n e l B l o c k e r s B e p r i d i l ; I s r a p i d i n e ; N i c a r d i p i n e D i u r e t i c s I n d a p a m i d e ; M o e x i p r i l / H C T Z H o r m o n e s O c t r e o t i d e ; V a s o p r e s s i n I m m u n o s u p p r e s s i v e s T a c r o l i m u s M i g r a i n e : S e r o t o n i n R e c e p t o r A g o n i s t s Z o l m i t r i p t a n ; N a r a t r i p t a n ; S u m a t r i p t a n M u s c l e R e l a x a n t T i z a n i d i n e N a r c o t i c D e t o x i f i c a t i o n L e v o m e t h a d y l P s y c h o t h e r a p e u t i c s : A n t i d e p r e s s a n t s A m i t r i p t y l i n e ; D e s i p r a m i n e ; F l u o x e t i n e ; I m i p r a m i n e ; V e n l a f a x i n e A n t i p s y c h o t i c C h l o r p r o m a z i n e ; H a l o p e r i d o l ; P i m o z i d e ; Q u e t i a p i n e ; R i s p e r i d o n e ; T h i o r i d a z i n e A n t i a n x i e t y D o x e p i n A n t i m a n i c L i t h i u m R e s p i r a t o r y : S y m p a t h o m i m e t i c s S a l m e t e r o l S e d a t i v e / H y p n o t i c s C h l o r a l h y d r a t e Drugs Which Prolong the QTc http://www.dml.georgetown.edu/depts/pharmacology/torsades.html http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/publicat/adrv8n1_e.html

7. QT Prolongation & Torsades de Pointes • Congenital LQTS • Acquired LQTS • Drugs • Bradycardia • Hypokalemia • CHF & LVH

9. Action Potential and Ionic Currents

10. Ventricular Action Potential Ca++ Na+ IKr IKs

11. Mechanisms Of Drug - Induced QT Prolongation and Tdp • Block of repolarizing K+ currents • Stimulation of ICa-l • Stimulation of INa

12. HERG Channel

13. Mechanism of Torsades de Pointes • Early afterdepolarizations • Transmural reentry

14. Yan & Antzelevitch Circulation. 1998;98:1921-1927

15. Yan & Antzelevitch Circulation. 1998;98:1928-1936

16. Torsades de Pointes EPI M ENDO

17. Torsades de Pointes

18. ECG - QT Interval

19. Automated QT and QTc Analysis • Reliable with normal T waves at physiologic heart rates • Unreliable: • High heart rates • Abnormal T waves • Prominent U waves • T-U wave complex morphology

21. QT  RR HR 66 bpm HR 83 bpm Rate-Corrected QT Interval (QTc) • QT Interval corrected for heart rate = QTc (Bazett) QTc = • General Population Average QTc = 380-400 msec • Bazett correction has major limitations

22. QT Correction Formulae

23. Normal QTc Interval - Criteria QTc (msec) Male Female Normal <430 <450 Borderline 431-450 451-470 Prolonged >450 >470

24. Percent of Patients with QTc or QT> 500 msec (%) 100 89.5 89.5 80.2 75.5 QTc 75 50 QT 25 0 Antiarrhythmic Drugs Non-Antiarrhythmic Drugs (N= 332) (N=189) QT Intervals in Drug Induced TdP Makkar et al JAMA 1993; 270: 2590-2597. Bednar & Ruskin (personal communication)

25. 70 67.2 75 Female 50 32.8 30 Male 25 0 Antiarrhythmics Non-Antiarrhythmics (N=189) (N=332) Drug-Induced TdP - Gender Distribution Makkar et al JAMA 1993; 270: 2590-2597. Bednar & Ruskin (personal communication)

26. TdP - High Risk Drugs (> 1%) Therapeutic Effect Is Linked to IKr Block • Quinidine • Disopyramide • Sotalol • Ibutilide • Dofetilide

27. TdP - Low Risk Drugs (< 0.1%) Therapeutic Effect Is Independent of IKr Block • Antihistamines • Antibiotics • Antiviral agents • Psychotropics • Many others

28. Drug-Induced Torsades de Pointes • Primary: Drug effect (IKr block) • Secondary: Effect Amplifiers • Bradycardia • Hypokalemia • Heart disease (LVH or CHF) • Atrial fibrillation • Female gender • Undetected HERG mutation • High doses • Metabolic inhibitors (PK) • Concomitant IKr blockers (PD)

29. Effect of EC K+ on Drug Induced IKr Block Circulation 1996 Feb 1;93(3):407-11Yang T, Roden DM

30. Hepatic drug metabolism Roden, D. Cardiac Electrophysiology (Zipes & Jalife) Ch XIV WB Saunders 2000

31. CYP450 3A4 Inhibitors • Amiodarone • Cimetidine • Fluoxetine • Grapefruit juice • Protease inhibitors • Ketoconazole; itraconazole • Macrolide antibiotics (not Azithromycin) • Nefazadone

32. Drug Induced Torsades de Pointes Drug EP Effects Metabolic Liability Terfenadine IKr blocker 3A4 substrate Cisapride IKr blocker 3A4 substrate Mibefradil IKr blocker 3A4 inhibitor Erythromycin IKr blocker 3A4 inhibitor Astemizole IKr blocker 3A4 substrate Dofetilide IKr blocker Renal excretion Sotalol IKr blocker Renal excretion

33. 90 80 70 60 50 Terfenadine Terfen & Keto 40 30 20 10 0 QTc Changes with Terfenadine Effect of CYP3A4 Inhibition with Ketoconazole Change In QTc (msec)

34. Q T c C h a n g e ( m s e c ) S a f e t y A b s e n c e o f 6 - 8 m s e c * N o e v i d e n c e o f i n c r e a s e d M e t a b o l i c I n h i b i t o r ¨ m o r t a l i t y i n p r e s c r i p t i o n - a v e r a g e a c r o s s d o s i n g b a s e d s t u d i e s i n t e r v a l N ~ 1 8 0 , 0 0 0 1 8 m s e c ¨ o n e h o u r p o s t d o s e Terfenadine (Seldane) 60 mg BID > 100 million prescriptions ( C O M P A S S ) * * N ~ 2 0 , 0 0 0 ( H C H P ) * * * P r e s e n c e o f 8 2 m s e c ( n o n - p e a k ) * * * * I n c r e a s e d r i s k o f s u d d e n M e t a b o l i c I n h i b i t o r ( m o r e t h a n t w e n t y - f o l d d e a t h l e d t o w i t h d r a w a l i n c r e a s e i n c o n c e n t r a t i o n ) * Pratt CM, et al. Am Heart J 1996; 131:472-480 ** Pratt CM, et al. Am J Cardiol 1994; 73: 346-352 *** Hanrahan JP, et al. Ann Epidem 1995; 5:201-209 **** Honig PK, et al. JAMA 1993; 269:1513-1518

35. Cisapride (Propulsid) • Gastric prokinetic (GERD) • IKr blocker (modest QT effect) • CYP 3A4 substrate • Clarithromycin - 3X increase in conc • Ketoconazole - 8X increase in conc • 30 million Rx’s since 1993; no arrhythmia signal in large database review • 1993-1999: 270 cases of serious arrhythmias reported to FDA (70 deaths) • One AE per 111,000 and one fatality per 428,000 prescriptions (undetectable in controlled trials)

36. TdP: Multiple-Hit Hypothesis • Drug exposure (IKr blocker) • Second risk factor • Bradycardia • Hypokalemia • Female gender • Metabolic inhibitor • Other QT prolonging drugs • Underlying heart disease (CHF, LVH, AF) • Genetic polymorphism (IKr or IKs)

37. Drugs Withdrawn for TdP Drug Class Date Withdrawn Terfenadine Antihistamine Feb 1998 Sertindole Antipsychotic Dec 1998 Astemizole Antihistamine Jun 1999 GrepafloxacinAntibiotic Nov 1999 Cisapride GI Prokinetic July 2000

38. GAO 01-286R 1/19/01

39. Drug Induced QT Prolongation Preclinical Screeing • In vitro ion channels effects • IKr - cloned HERG (HEK or AT-1 cells) • Ica & INa • In vitro APD effects • Isolated myocytes (dog,rabbit,g. pig) • Purkinje fibers (dog,rabbit) • Papillary muscle (guinea pig) • Wide range of concentrations (100-1000X) • Wide range of rates • Metabolites

40. Other In vitro models • LV wedge (perfused canine) • Perfused rabbit heart ( HR & K+) • In vivo models • Conscious rabbit • Anesthetized methoxamine sensitized rabbit • Canine chronic AV block Drug Induced QT Prolongation Preclinical Screeing

41. Evaluation of New Drugs - Risk Assessment • Preclinical profile • QT effects in humans • Mean & mean max changes c/w PBO • Categorical analysis • Outliers • Special populations • Torsades de Pointes • VT, VF & cardaic arrest • Syncope • Sudden death

42. Drug-Induced TdP • Drug - drug interactions • Pharmacokinetic • Pharmacodynamic • Drug - gene interactions • Genetic polymorphisms • Acquired repolarization reserve (CHF)

43. Drugs Which Cause TdP • Almost all are IKr blockers • Preclinical profile cannot exclude risk • Many are CYP 450 3A4 substrates • Numerous cofactors enhance risk • TdP rarely detected in drug development

44. Drug Induced QT Prolongation • Preclinical findings • QT effects in humans • Adverse event profile • Therapeutic target(s) • Relative efficacy • Unique advantages • Alternative options • Risk:benefit assessment

46. Post-CABG Day 4(on Fluconazole) QT=380 QTc=460 QT=380 QTc=460

47. Post-CABG Day 3 QTc 516 ms on fluconazole QTc normal preop

50. Amiodarone QT 621 QTc 747 HR 87 Long-short -> TdP