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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 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