1、White PaperConcentration-QT Modeling:An Efficient Alternative for Clinical Development Table of contentsIntroduction 1Understanding the effect of drugs on ventricular repolarization 2Trial design considerations for C-QT studies 4The C-QT study population 7C-QT or TQT,that is the question?8Regulatory
2、 considerations 9IQVIA experience with C-QT studies 10Conclusion 11References 12About the authors 14 |1Multiple drugs are known to cause heart rhythm disturbances,including the potentially fatal ventricular arrhythmia Torsades de Pointes(TdP)shown in Figure 1.1 Evaluating a drug candidate for TdP ri
3、sk is critically important but can be challenging because TdP is rare.The overall incidence of TdP is largely unknown because the condition is transient and often does not cause symptoms,but estimates range from 0.004%to 0.343%annually.The challenge of detecting TdP risk is exemplified by the post-m
4、arketing withdrawal of prenylamine,terfenadine and cisapride after they were associated with ventricular arrhythmias and sudden cardiac death,despite no signal of this in clinical development.2 Figure 1.Electrical activity of the normal heartbeat and ventricular tachycardia.A:In a healthy heart rhyt
5、hm,atrial depolarization(P wave)is followed by ventricular depolarization(QRS complex)and repolarization(T wave).This sequence of electrical activity coordinates heart muscle contractions needed to pump blood.B:In ventricular tachycardia,electrical activity becomes uncoordinated,and the QRS complex
6、is widened.C:In Torsades de Pointes French for“twisting of the points”a potentially fatal form of ventricular tachycardia,the QRS complex appears to rotate around a horizontal axis.The prolonged QT interval is a well-established biomarker for TdP,seen on an electrocardiogram(ECG)as the time between
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