Drug‐Induced Torsades de Pointes and Implications for Drug Development

Abstract

Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug‐induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug‐induced repolarization changes, their preclinical and clinical evaluation, and the risk‐to‐benefit interpretation of drug‐induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug‐related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug‐induced torsades within the larger evaluation of drug‐related risks and benefits. (J Cardiovasc Electrophysiol, Vol. 15, pp. 475‐495, April 2004)

Tomenendalova J: How to approach the QT interval in dogs - the state of the heart: a review

“…A similar situation has been determined in dogs, where the lead CV 5 RL seems to produce less intra-and inter-animal variability as it well defined at the end (Nahas and Geffray, 2004). Other authors claim that the QTi can be measured from the longest QT period in a strip if the lead is well defined or not (Fenichel et al, 2004). Careful superimposition of different digitally and simultaneously recorded leads seems to solve the problem of lead selection and frequently makes the Q wave onset on T wave offset easier to detect (Fenichel et al, 2004).…”

“…Most reports in the human literature measure one QTi in the lead II at a speed of 25mm/s (Moss, 1999;Friedman et al, 2003), which can compromise the accuracy of measurement. Other reports recommend this measurement in leads II, V 2 and V 3 , because the T wave is always well defined and often reaches the maximal amplitude in these leads (Elming et al, 2003;Viskin et al, 2003;Vohra, 2003;Fenichel et al, 2004;Charbit et al, 2006). A similar situation has been determined in dogs, where the lead CV 5 RL seems to produce less intra-and inter-animal variability as it well defined at the end (Nahas and Geffray, 2004).…”

“…Other authors claim that the QTi can be measured from the longest QT period in a strip if the lead is well defined or not (Fenichel et al, 2004). Careful superimposition of different digitally and simultaneously recorded leads seems to solve the problem of lead selection and frequently makes the Q wave onset on T wave offset easier to detect (Fenichel et al, 2004). This is an interesting method for validation because dogs can show different T wave configurations that can change on a daily basis in simultaneous leads, including precordial leads, and has been the selected method in our practices.…”

Human Pluripotent Stem Cell-Derived Cardiomyocytes: Maturity and Electrophysiology

“…With regard to proarrhythmic potential, the QT interval is the cornerstone of the guidelines for the assessment of new chemical compounds (ICH, 2005, ICH, 2005. A number of drugs can potentially prolong the QT interval (Fenichel et al, 2004, and it is also a leading cause for use restriction and market withdrawal , the International Conference of Harmonization has defined the evaluation of this risk for new chemical entities as standard preclinical process (Bode & Olejniczak, 2002, Cavero & Crumb, 2005. Delayed rectifier potassium current (I Kr ) is responsible in part for the repolarization of the action potential (Vandenberg et al, 2001, Pollard et al, 2008.…”

Torsades de Pointes in the Guinea-Pig Heart

“…It is increasingly recognized that certain cardiovascular and non-cardiovascular medicines may induce a potentially life threatening form of ventricular tachyarrhythmia known as torsades de pointes (TdP; [1,2]). This realization led to the withdrawal of a number of drugs from the market, and proarrhythmic testing of a drug candidate is routinely performed today using a battery of pre-clinical tests.…”