Proarrhythmic Cardiac Safety

Repolarization of cardiac myocytes is primarily influenced by the outward flow of potassium ions through potassium channels, i.e., translocation of potassium ions from the intracellular side of the plasma membrane to the extracellular side. Multiple forms of potassium ion channels mediate cardiac repolarization, and each of these is associated with a particular ionic current. One of these ionic currents, has been of particular interest in the field of proarrhythmic cardiac safety. 

The discipline of cardiac electrophysiology studies how the cardiac conduction system facilitates the flow of electrical stimuli across cardiac tissues. The discipline is employed in clinical practice for the diagnosis of cardiac rhythm abnormalities and pathophysiology and can also be used in proarrhythmic cardiac safety evaluations ... 

The Proarrhythmic Cardiac Safety Regulatory Landscape Circa 2005-2015 Drug-Induced hERG Channel Block and the Thorough QT/QTc Study... 

The Proarrhythmic Cardiac Safety Regulatory Landscape Circa 2005-2015... 

The first part of this chapter s title, The Proarrhythmic Cardiac Safety Regulatory Landscape circa 2005-2015, provides a clue that, as we write this chapter in January 2016, this landscape is in a state of transformation. As discussed in the following two chapters, initiatives are underway to modify both nonclinical and preapproval clinical assessments of a drug s proarrhythmic liability. Since an alternative approach in the preapproval clinical domain is closer to formal regulatory approval, this is discussed in Chap. 8 an alternative nonclinical approach is then discussed in Chap. 9. Nonetheless, the topic of this chapter, cardiac safety circa 2005-2015, remains of considerable importance. Events and regulatory science discussed herein address the origins of the formalized domain of proarrhythmic cardiac safety, a decade s work in this domain, and reasons why modifications to the ICH S7B and ICH E14 regulatory landscape have been deemed desirable. 

Table 7.1 presents a timehne of important events in the development of the current landscape, and, since methodologies and regulatory landscapes are evolving as we are writing this chapter, the potential future proarrhythmic cardiac safety regulatory landscape. 

Turner JR, Britto M, Cabell CH et al (2015) Evolution of the proarrhythmic cardiac safety regulatory landscape the likely revision of ICH Guideline E14 and its consequences. J Clin Stud 7(6) 52-58... 

The modifications of the proarrhythmic cardiac safety paradigm discussed in this chapter facilitate a move away from an environment in which a dedicated TQT study is conducted in later phases of clinical development towards one in which intensive ECG evaluation is conducted in the early phase of drug development during first-in-human studies. 

This book is a self-contained introduction to, and exposition of, the field of biophar-maceutical cardiovascular safety. While drugs for cardiovascular diseases or conditions of clinical concern are expected to affect the cardiovascular system, drugs for other indications are not. However, there is always the possibility that a noncardio-vascular drug can exert a deleterious influence on one or more parts of the cardiovascular system, and, while rare, some drug-induced cardiac adverse events can be fatal. The field of cardiovascular safety, of which proarrhythmic cardiac safety is an important component, has therefore assumed considerable importance in contemporary drug development and therapeutic use. Not everyone needs to be an expert in cardiovascular safety (and this book by itself does not presume to make anyone an expert), but everyone can benefit from a fundamental knowledge of the field. 

---