Keeping the Rhythm: hERG and Beyond in Cardiovascular Safety Pharmacology

Clemens Möller

Disclosures

Expert Rev Clin Pharmacol. 2010;3(3):321-329. 

In This Article

Five-year View

Scientific research has given us a fairly good, and still continuously improving, knowledge about TdP and other cardiac arrhythmias and malfunctions and their molecular causes. These understandings are also increasingly considered by regulatory authorities concerned with cardiac safety pharmacology. It is important to keep in mind that (in vitro) hERG channel blockade, as well as (in vivo) QT interval prolongation, only gives indications of possible cardiac side effects. Although the currently effective clinical[72,73] and preclinical regulatory guidelines are still focusing on these surrogate markers, evidence exists that regulatory authorities are adopting a more differentiated view.[1,18] In particular, the currently effective ICH S7B document is now already 5 years old, and it should be clear that this should be read as what it is: a guidance, not a doctrine.[32] Thus, the guidelines do leave the necessary freedom to follow latest scientific insights. In particular, the predictivity of the widely used QT interval as a surrogate marker for proarrhythmic risk is increasingly questioned. Other parameters, including triangulation of the action potential[59,60] and effects on transmural dispersion,[74,75] have been shown to be much better predictors of torsadogenicity, while the QT interval has been shown to yield a number of false positives and false negatives[64] in predicting the proarrhythmic effects of compounds.

Development and validation of novel cardiac test systems is ongoing, and while these may not be meant to replace hERG channel electrophysiology, they are expected to deliver valuable additional information. In addition, structural details of the hERG channel pore are being unraveled and will increasingly help medicinal chemists to design compounds with reduced hERG liabilities, keeping the target affinity intact.

Significant hope is placed in human stem cell-derived cardiac myocytes, which should prove a valuable source of high-quality homogenous cardiac cells. Owing to the importance of the hERG channel for drug-induced arrhythmias, it could be expected that investigations in myocytes may not replace electrophysiological hERG channel investigations in heterologous expression systems. Rather, electrophysiological action potential recordings of myocytes, be it by patch clamping, or by electrode arrays, provide information beyond pure hERG channel blockade.[76] Thus, it allows us to gain information on the activity of compounds on the 'complex concert of ion channels', in their more native environment than by heterologous expression. Cellular test systems using stem cell-derived ventricular myocytes could, therefore, potentially reduce the requirement for testing of selected compounds on individual cardiac ion channels in addition to the hERG channel, and could potentially help to increase the cardiac safety of drugs.

Cardiac electrophysiology, including proarrhythmia, will always remain a complex concert of many ion channels, with complex mechanisms operating within a complex organ and a complex species. Therefore, one single gold-standard test system that can be applied exclusively should, not be expected to become available. Instead, the existing integrated risk-assessment approach, balancing information from different assays, does appear a reasonable approach for assessing the potential cardiac effects of drugs. Future experiences, stored and accessed in dedicated connected drug safety vigilance databases, will help to validate the new experimental tools, balance and weigh the information from them for an integrated risk assessment, and unravel the correlations between estimated risks, observed postmarketing incidences and corresponding drug safety.

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