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

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

2. Drugs Withdrawn for Potential Health Risk (Cardiac Arrest and Death) Drug Class Date Withdrawn Terfenadine Antihistamine Feb 1998 Sertindole Antipsychotic Dec 1998 Astemizole Antihistamine Jun 1999 GrepafloxacinAntibiotic Nov 1999 Cisapride GI Prokinetic July 2000

3. Electrical Properties of the Heart: Impulses originate in the SA node Internodal pathways AV node Bundle of His Cardiac conduction pathways. (Quoted from Core Concepts in Pharmacology, 2003) Left and right bundle branches The conduction system as a whole innervates the mechanical myocardium and serves to initiate excitation–contraction coupling Purkinjie fibers

4. Action potential of heart tissue The heart employs two kinds of action potentials: Pacemaker Cells Action Potential: Non-Pacemaker Cells Action Potential: • 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) • 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)

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

6. 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.

7. QT  RR HR 66 bpm HR 83 bpm 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)

8. 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

9. Torsades de Pointes • Potentially life threatening due to risk of VF and cardiac arrest • Not highly predictable despite known risk factors

10. 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 prolongation QTc prolongation → early afterdepolarizations (EAD) → reentry →torsade de pointes (TdP) and fatal ventricular arrhythmias [sudden cardiac death]

11. 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)

12. b. Simultaneous use of multiple QTc prolonging drugs • Pharmacodynamic interactions • 2 drugs with QT prolonging effects e.gsotalol, 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 • 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)

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

14. 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)

15. TdP - High Risk Drugs (> 1%) Main Action Linked to IKr Block • Quinidine • Disopyramide • Sotalol • Ibutilide • Dofetilide

16. TdP - Low Risk Drugs (< 0.1%) Main Action Independentof IKr Block • Antihistamines • Antibiotics • Antiviral agents • Psychotropics • Many others

17. 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

18. 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