QTc INTERVAL AND RISK AJC 1993; 72:21B

Relative Risk of Arrhythmias = 1.052x

where x = msec increase/10 above QTc 440msec

QTc = 440msec Risk = 1.0520 = 1.0

QTc = 500msec Risk = 1.0526 = 1.4

QTc = 640msec Risk = 1.05220= 2.8

DRUGS AND QTc: ISSUES

1. QTc prolongation and risk: exponential 2. Magnitude of the QTc signal: mean QTc; range & outliers3. Drug effect on QTc: a. direct: e.g., sotalol, cisapride b. indirect (interaction): i) drug-drug: terfenadine + ketoconazole ii) drug-gene: LQTS mutation/polymorphism

DRUGS AND QTc: Questions

1. Do the pre-clinical studies indicate an effect on ventricular repolarization?

2. Do clinical studies indicate a QTc signal?

3. What is the magnitude of the QTc signal?

4. Are there potential drug interactions?

5. Does the drug have unique characteristics?