Evaluation of Cardiac Safety by ECG Findings: Focus on QTc Duration

Drugs Withdrawn for Potential Health Risk (Cardiac Arrest and Death)

Drug Class Date Withdrawn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

Cardiac conduction pathways.(Quoted from Core Concepts in Pharmacology, 2003)

Electrical Properties of the Heart:

The conduction system as a whole innervates the mechanical myocardium and serves to initiate excitation–

contraction coupling

Impulses originate in the SA node

Internodal pathways

AV node

Bundle of His

Left and right bundle branches

Purkinjie fibers

Action potential of heart tissue

The heart employs two kinds of action potentials:

Non-Pacemaker Cells Action Potential:

-Atrial and ventricular tissue, His-Purkinje system-Five phases (0-4)-Rapid depolarizing current mainly by Na+ influx-Only respond to but no spontaneous depolarization-Resting membrane potential more negative (-90 mV)

-Nodal tissues (SA, AV,..)

-Four phases (0-4) (1 is absent)-Slow depolarizing current mainly by Ca++ influx-Spontaneous phase 4 depolarization-Resting membrane potential less negative (-60 mV)

Pacemaker Cells Action Potential:

ECG:provides a graphic representation of cardiac electrical activity. It is useful in identifying dysrhythmias and monitoring responses to therapy.

Electric Activity ms Interval

Atrial Depolarization 120- 200

P wave

VentricularDepolarization

<140 QRS wave

VentricularRepolarization

<400 T wave

QT interval: • Defines as the time between the onset of the QRS complex and the

completion of the T wave. • Measures the time between the onset and end of ventricular electrical

activity• Measures time of ventricular depolarization and repolarization.• Drugs that delay ventricular repolarization prolong this interval.

Rate-Corrected QT Interval (QTc)

• Measured QT interval decreases when the heart beats more rapidly; therefore the QT interval should be corrected for heart rate

• QT Interval corrected for heart rate = QTc (Bazett) = • General Population Average QTc = 380-400 msec• Bazett correction has major limitations (undercorrects at low HR)

HR 66 bpm

HR 83 bpm

QT RR

Importance of Cardiac Safety Issue of New Therapy and Prolongation of the QTc Interval. Why?

Increased risk of torsades de pointes (potentially fatal polymorphic ventricular tachycardia) as QTc interval increases QTc <500 msec

Torsades de Pointes

Potentially life threatening due to risk of VF and cardiac arrest

Not highly predictable despite known risk factors

Mechanisms Of Drug-Induced QT Prolongation and Tdp• Block of repolarizing K+ currents

• Stimulation of ICa-l

• Stimulation of INa

Excessive intracellular positive ions → delayed ventricular repolarization and QTc interval prolongationQTc prolongation → early afterdepolarizations (EAD) → reentry → torsade de pointes (TdP) and fatal ventricular arrhythmias [sudden cardiac death]

Drug-induced QTc prolongation a. Both cardiac and non-cardiac drugs have been

implicated. i. Class I and III antiarrythmics (e.g. quinidine, sotalol,

amiodarone) ii. Psychotropics

Antipsychotics [e.g. thioridazine, pimozide, haloperidol (IV), ziprasidone, quetiapine]

Antidepressants (TCAs, SSRIs) iii. Opiate agonists (methadone) iv. Anti-infectives (e.g. moxifloxacin, clarithromycin) v. Antihistamines (e.g. astemizole, terfenadine)

b. Simultaneous use of multiple QTc prolonging drugs i. Pharmacodynamic interactions2 drugs with QT prolonging effects e.g sotalol, a Class

III antiarrhythmic with moxifloxacin, a fluoroquinolone with mild QTc-prolonging effects

drugs with QT prolonging effect in presence of other risk factor e.g. hypokalemia or hypomagnesmia

ii. Pharmacokinetic interactions (inhibition of drug metabolism or clearance)

(Patient taking terfenadine, an antihistamine with potent Ikr-blocking activity, and then prescribed ketoconazole, a potent CYP3A4 inhibitor, which significantly increases terfenadine levels)

iii. High concentrations of the drugs due to overdose or rapid infusion

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)

TdP - High Risk Drugs (< 1%)

Quinidine Disopyramide Sotalol Ibutilide Dofetilide

Main Action Linked to IKr Block

TdP - Low Risk Drugs (< 0.1%)

Antihistamines Antibiotics Antiviral agents Psychotropics Many others

Main Action Independent of IKr 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

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 C hang e (ms ec ) S afety

Abs enc e ofMetabolic Inhibitor

6-8 msec*¨ average across dos ing interval

18 msec¨ one hour post dose

No evidence of increasedmortality in prescription-based studies N~180,000 (C OMP AS S )** N~20,000 (HC HP )***

P res enc e ofMetabolic Inhibitor

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

Increased risk of suddendeath led to withdrawal