THE CARDIAC SAFETY ISSUE:
QT Prolongation (Long QT) from non-antiarrythmic drugs ("nards")

• QT prolongation due to "nards" is:

  • A serious complication of drugs due to impaired repolarization
  • Associated with an increased risk of lethal ventricular arrhythmias
  • Thus far, always associated with block of hERG, the cardiac ion channel responsible for I_kr , the rapidly repolarizing potassium current
• A 5-10 millisecond increase in rate-corrected QT (QTc) may indicate risk of ventricular arrhythmia particularly torsades de pointes (tdp)
• Incidence of TdP is too low to be detected in clinical trials
• More than 40 marketed drugs have been associated with hERG channel block, QT prolongation and TdP
• Heightened regulatory awareness has had significant impact on drug development schedules, approval and labeling
• During drug development, nonclinical safety testing can :
  • Identify potentially lethal drugs that block the hERG channel
  • Identify drugs without hERG or QT risk
  • Produce savings in time & development costs

  During drug discovery, nonclinical safety testing can :

  • Identify the safest candidates for lead development
  • Produce savings in time & costs

ION CHANNELS, ACTION POTENTIALS AND
QT PROLONGATION
Voltage-dependent ion channels are proteins that span the cell surface membranes in excitable tissue such as the heart. Ions passing though channels form the basis of the cardiac action potential. Influx of Na+ and Ca2+ ions, respectively, control the depolarizing upstroke and plateau phases of the action potential. K+ ion efflux repolarizes the cell membrane, terminates the action potential, and allows relaxation of the muscle. A rapid component of the repolarizing current (IKr) flows through the K+ channel encoded by the human ether-à-go-go-related gene (hERG). A slow component (IKs) passes through the K+ channel encoded by KvLQT1 and the accessory minK gene. Impaired repolarization can prolong the duration of the action potential, delay relaxation and promote disturbances of the heart beat. Action potential prolongation is detected clinically as a lengthening of the QT interval measured on the electrocardiogram (ECG).

DRUG-INDUCED LONG QT SYNDROME & THE HERG ION CHANNEL
Many antiarrhythmic drugs act by slowing cardiac repolarization and prolonging the QT interval of the ECG. This effect may be proarrhythmic but is manageable if anticipated. The risk is more significant for non-antiarrhythmic drugs that impair cardiac repolarization because the effect is unanticipated. The vast majority of non-antiarrhythmic drugs that prolong the QT interval have been found to specifically interact with the hERG channel. As a result, testing a drug's ability to block hERG current has become a very important nonclinical predictive test.