Drug-Induced QT Interval Prolongation and

Torsades de Pointes

Drug-Induced Torsades de Pointes Low frequency event Potentially life threatening Not highly predictable despite

known risk factors

QT Prolongation & Torsades de Pointes

Cardiac electrophysiology Clinical pharmacology Genetics Regulatory medicine Clinical Practice

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

Drugs Which Prolong the QTc

http://www.dml.georgetown.edu/depts/pharmacology/torsades.htmlhttp://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/publicat/adrv8n1_e.html

Anticonvulsants Fosphenytoin; FelbamateAntihistamines Azelastine; ClemastineAnti-Infectives Amantadine; Clarithromycin; Chloroquine; Foscarnet;

Erythromycin; Halofantrine; Mefloquine; Moxifloxacin;Pentamidine; Sparfloxacin; Quinine; Trimethoprim-Sulfamethoxazole, Ketoconazole

Antineoplastics TamoxifenCardiovascular: Antiarrhythmics Amiodarone; Bretylium; Disopyramide; Flecainide;

Ibutilide; Procainamide; Quinidine; Sotalol; Dofetilide Calcium Channel Blockers Bepridil; Israpidine; Nicardipine Diuretics Indapamide; Moexipril/HCTZHormones Octreotide; VasopressinImmunosuppressives TacrolimusMigraine: Serotonin Receptor Agonists Zolmitriptan; Naratriptan; SumatriptanMuscle Relaxant TizanidineNarcotic Detoxification LevomethadylPsychotherapeutics: Antidepressants Amitriptyline; Desipramine; Fluoxetine; Imipramine; Venlafaxine Antipsychotic Chlorpromazine; Haloperidol; Pimozide; Quetiapine;

Risperidone; Thioridazine Antianxiety Doxepin Antimanic LithiumRespiratory: Sympathomimetics SalmeterolSedative/Hypnotics Chloral hydrate

QT Prolongation & Torsades de Pointes

Congenital LQTS Acquired LQTS

Drugs Bradycardia Hypokalemia CHF & LVH

Action Potential and

Ionic Currents

Ventricular Action Potential

Na+

IKr

Ca++

IKs

Mechanisms Of Drug - Induced QT Prolongation and Tdp

Block of repolarizing K+ currents

Stimulation of ICa-l

Stimulation of INa

HERG Channel

Mechanism of Torsades de Pointes

Early afterdepolarizations

Transmural reentry

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

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

Torsades de Pointes

EPI

M

ENDO

Torsades de Pointes

ECG - QT Interval

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

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

HR 66 bpm

HR 83 bpm

QT

RR

QT Correction Formulae

Original CohortFormula Mathematical

Expression for QTc NMean Age

(Range) (years)

Log-Linear

Bazett QT / (RR) 0.5 39 26 (<14-53)

Fridericia QT / (RR) 0.33 50 26 (2-81)

Baseline correction QT / (RR)0.37 NA NA

Linear

Framingham QT + 0.154 (1 – RR) 5,018 44 (28-62)

Hodges QT + 1.75 (HR – 60) 607 (20’s-80’s)

Normal QTc Interval - Criteria

QTc (msec) Male Female

Normal <430 <450

Borderline 431-450 451-470

Prolonged >450 >470

QT Intervals in Drug Induced TdP

89.580.2

89.5

75.5

0

25

50

75

100

Antiarrhythmic Drugs Non-Antiarrhythmic Drugs(N= 332) (N=189)

QTc

QT

Percent of Patients with QTc or QT> 500 msec (%)

Makkar et al JAMA 1993; 270: 2590-2597.Bednar & Ruskin (personal communication)

70

30

67.2

32.8

0

25

50

75

Antiarrhythmics Non-Antiarrhythmics(N=332) (N=189)

Female

Male

Drug-Induced TdP - Gender Distribution

Makkar et al JAMA 1993; 270: 2590-2597.Bednar & Ruskin (personal communication)

TdP - High Risk Drugs (> 1%)

Quinidine Disopyramide

Sotalol

Ibutilide

Dofetilide

Therapeutic Effect Is Linked to IKr Block

TdP - Low Risk Drugs (< 0.1%)

Antihistamines Antibiotics Antiviral agents Psychotropics Many others

Therapeutic Effect Is Independent of IKr Block

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)

Effect of EC K+ on Drug Induced IKr Block

Circulation 1996 Feb 1;93(3):407-11Yang T, Roden DM

Hepatic drugmetabolism

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

CYP450 3A4 Inhibitors

Amiodarone Cimetidine Fluoxetine Grapefruit juice Protease inhibitors Ketoconazole; itraconazole Macrolide antibiotics (not Azithromycin) Nefazadone

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

QTc Changes with Terfenadine Effect of CYP3A4 Inhibition with Ketoconazole

0

10

20

30

40

50

60

70

80

90

TerfenadineTerfen & Keto

ChangeIn QTc(msec)

Terfenadine (Seldane) 60 mg BID

* 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

> 100 million prescriptions

QTc Change (msec) Safety

Absence ofMetabolic Inhibitor

6-8 msec* average across dosing interval

18 msec one hour post dose

No evidence of increasedmortality in prescription-based studies N~180,000 (COMPASS)** N~20,000 (HCHP)***

Presence ofMetabolic Inhibitor

82 msec (non-peak)****(more than twenty-foldincrease in concentration)

Increased risk of suddendeath led to withdrawal

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)

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)

Drugs Withdrawn for TdP

Drug Class Date Withdrawn

Terfenadine Antihistamine Feb 1998

Sertindole Antipsychotic Dec 1998

Astemizole Antihistamine Jun 1999

Grepafloxacin Antibiotic Nov 1999

Cisapride GI Prokinetic July 2000

GAO01-286R1/19/01

Drug Induced QT ProlongationPreclinical 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

Drug Induced QT ProlongationPreclinical Screeing

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

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

Drug-Induced TdP

Drug - drug interactions Pharmacokinetic Pharmacodynamic

Drug - gene interactions Genetic polymorphisms Acquired repolarization reserve (CHF)

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

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

Post-CABG Day 4 (on Fluconazole)

QT=380 QTc=460QT=380 QTc=460

QTc 516 ms on fluconazoleQTc normal preop

Post-CABG Day 3

Amiodarone

QT 621QTc 747HR 87

Long-short-> TdP