REGULATION

Although LQTS was named after the prolongation of the QT interval, its prolongation is only a marker for risk rather than a cause of arrhythmia. Use of the QT interval as a marker for risk is complicated because it can be changed by normal phenomena in healthy, risk-free individuals.  For example, as the heart rate increases, the QT interval shortens, so a variety of correction calculations (QTc) now exist.  In some cases QT intervals are misleading as to the torsadogenic risks of a compound [Hondeghem, 2006; Hondeghem et al., 2001; Witchel et al., 2003].  The discontinuity between risk factors (such as a prolonged QT interval) and the actual occurrence of arrhythmias may exist because arrhythmias might not occur until the heart has experienced “three hits”, with hERG-blockade and its consequent myocardial instability being only one hit [Keating and Sanguinetti, 2001].  It has been proposed that the hERG-derived risk of arrhythmogenesis arises from hERG blockade inducing myocardial electrical instability; arrhythmias might not be triggered until other conditions are met, such as emotions eliciting physiological arousal [Lown, 1987].  The autonomic nervous system was thought to be the primary source of arrhythmogenic risk in LQTS, and for decades the treatment for LQTS used to be prophylactic administration of beta blockers.  The fact that hERG is the genetic locus responsible for chromosome 7-associated long QT syndrome (LQT2; [Curran et al., 1995]) buttressed the controversial idea that LQTS was caused by anomalies in repolarisation of the myocardium [Sanguinetti and Keating, 1997] rather  than by unbalanced autonomic inputs into the heart [Schwartz et al., 1975].

Increased pressure from drug regulatory organisations has led to the risk of acquired LQTS affecting virtually every drug development programme.  The reasons for this are that drug-induced QT prolongation (leading to its concomitant arrhythmogenic risk) is so wide-spread and because it is not limited by either chemical or pharmacological class [Committee for Proprietary Medicinal Products, 1997].  However, the ICH (International Conference for Harmonisation) in their S7A guidelines pointed out in 2001, “There is no scientific consensus on the preferred approach to, or internationally recognized guidance on, addressing risks for repolarization-associated ventricular tachyarrhythmia (e.g., Torsade de Pointes)” [ICH, 2001].  Current regulatory measures, particularly in the USA, revolve around performing a Through QT study for each drug, which entails a clinical trial with time-matched measures of QT intervals verified by use of a positive control drug (usually moxifloxacin), and having a safety cut-off of a mean increase in QTc of 5 milliseconds; however, it is generally accepted that, for both cardiac and noncardiac drugs, QTc exceeds 500 milliseconds in ~ 90% of reported cases of drug-induced TdP [Bednar et al., 2002; Makkar et al., 1993], which is prolongation far in excess of 5 milliseconds above baseline — this number represents the limit of robust detection rather than an outright safety measure.  The regulatory goal is not to disqualify all drugs that prolong the QT interval by 5 ms, but to necessitate the accurate determination of QT liability and to engender a risk:benefit analysis.

The relationship between hERG block and arrhythmogenic risk is being further elucidated, and more affordable and rapid technologies for detecting hERG-derived arrhythmogenic risk are being developed. Without a model to create more accurate estimates of risk, very costly human clinical safety tests and attrition of new chemical entities will make drug development for disorders with low prevalence prohibitively expensive.  Too many compounds are rejected due to hERG liability; numbers quoted at meetings of pharmaceutical scientists can range from 40% to 70% of new chemical entities that are abandoned early in the drug development process after failing to have an adequate therapeutic window in light of hERG blockade.  Yet, not all drugs that block hERG have arrhythmogenic risk.  The simplified model of how hERG blockade leads inevitably to a risk of TdP in a small percentage of the population is sometimes employed as a heuristic for making financial, and even regulatory, decisions about compounds (see Figure 1 below).  However, many exceptions to this schematic exist.  We have proposed a more complicated schematic based on the idea of markers of risk.

This leads directly to more complicated models of arrhythmogenesis, but these more robust models do not as yet provide an easy go/no-go decision making tool.  The main theoretical problem with amassing a wide spectrum of pre-clinical data on many ion channels is in integrating the information.

Figure 1. The Old Scheme, which had many exceptions, compared to the New Marker Scheme.

 

 

References

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