Delays in cardiac repolarization can lead to life-threatening heart arrhythmias. As part of a typical drug development program, a sponsor must assess the potential for cardiac repolarization delays following administration of their investigational product. This assessment involves examination of the QT interval, which is the time during the heart’s electrical cycle from the beginning of the Q wave (depolarization of the interventricular septum) to the conclusion of the T wave (ventricular repolarization). Because the QT interval is strongly influenced by heart rate, the QT interval is often expressed as a “corrected” value (QTc) that takes heart rate into account.
For most drugs, the potential for pharmacologic prolongation of the QT interval involves performing a standalone thorough QT/QTc clinical study (TQT study). Pharmacokinetics (PK) is an integral part of TQT clinical studies. Characterization of the pharmacokinetic/pharmacodynamic concentration-response relationship (PK/PD) for QT/QTc prolongation is essential during these investigations. As such, careful consideration must be given to the timing of electrocardiogram (ECG) acquisition, the PK sampling schedule, and other study design elements. Depending upon the depth of existing knowledge around the PK behavior of the drug, pre-study simulations may be helpful for guiding study design and optimizing PK sample collection times.