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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

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drug induced 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
QT Prolongation & Torsades de Pointes
  • Cardiac electrophysiology
  • Clinical pharmacology
  • Genetics
  • Regulatory medicine
  • Clinical Practice
qt prolongation torsades de pointes5
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

Kathryn E. Williams:

SWR-May 16: update closer to AC date and add ‘version’ date to slide

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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

qt prolongation torsades de pointes7
QT Prolongation & Torsades de Pointes
  • Congenital LQTS
  • Acquired LQTS
    • Drugs
    • Bradycardia
    • Hypokalemia
    • CHF & LVH
mechanisms of drug induced qt prolongation and tdp
Mechanisms Of Drug - Induced QT Prolongation and Tdp
  • Block of repolarizing K+ currents
  • Stimulation of ICa-l
  • Stimulation of INa
slide13

Mechanism of Torsades de Pointes

  • Early afterdepolarizations
  • Transmural reentry
automated qt and qtc analysis
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

 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
normal qtc interval criteria
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

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)

slide25

70

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75

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50

32.8

30

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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)

tdp high risk drugs 1
TdP - High Risk Drugs (> 1%)

Therapeutic Effect Is Linked to IKr Block

  • Quinidine
  • Disopyramide
  • Sotalol
  • Ibutilide
  • Dofetilide
tdp low risk drugs 0 1
TdP - Low Risk Drugs (< 0.1%)

Therapeutic Effect Is Independent of IKr Block

  • Antihistamines
  • Antibiotics
  • Antiviral agents
  • Psychotropics
  • Many others
drug induced torsades de pointes28
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
Effect of EC K+ on Drug Induced IKr Block

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

slide30

Hepatic drug

metabolism

Roden, D. Cardiac Electrophysiology

(Zipes & Jalife) Ch XIV WB Saunders 2000

cyp450 3a4 inhibitors
CYP450 3A4 Inhibitors
  • Amiodarone
  • Cimetidine
  • Fluoxetine
  • Grapefruit juice
  • Protease inhibitors
  • Ketoconazole; itraconazole
  • Macrolide antibiotics (not Azithromycin)
  • Nefazadone
drug induced torsades de pointes32
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

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)

terfenadine seldane 60 mg bid

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> 100 million prescriptions

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* 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

cisapride propulsid
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
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
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

slide38

GAO

01-286R

1/19/01

slide39

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
slide40

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

evaluation of new drugs risk assessment
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-Induced TdP
  • Drug - drug interactions
    • Pharmacokinetic
    • Pharmacodynamic
  • Drug - gene interactions
    • Genetic polymorphisms
    • Acquired repolarization reserve (CHF)
drugs which cause tdp
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
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
slide46

Post-CABG Day 4(on Fluconazole)

QT=380 QTc=460

QT=380 QTc=460

slide47

Post-CABG Day 3

QTc 516 ms on fluconazole

QTc normal preop

amiodarone
Amiodarone

QT 621

QTc 747

HR 87

Long-short

-> TdP