hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 183

torsadogenic potential of a new drug can accumulate during post-marketing; a
much higher number of patients are exposed over longer periods of time, including
patients with risk factors, cardiovascular diseases, co-medication, metabolic
impairment and genetically determined enhanced susceptibility. The role of
inherited disturbances of the “rhythmome” (genes involved in the regulation of
cardiac rhythm) is increasingly better understood. It is estimated that 5% of patients
with drug-induced Tdp are silent carriers of gene mutations of cardiac ion channels.
In other words, we know which drugs are associated with Tdp and something of
how these drugs act to produce Tdp , but we do not understand individual patient
variability very well. Safety biomarkers, identified via pharmacogenetic testing of
patients with Tdp , help to characterize these individual liabilities for Tdp? The
repolarization reserve of the human heart is difficult to quantify, but it is the result
of a redundancy of physiological mechanisms. It is likely that risk factors and/or
genetic alterations in the target population reduce the repolarization reserve of the
heart and this leads in rare and specific cases to Tdp . Following this concept, it may
be questionable to use healthy young animals with an intact repolarization reserve
to predict the torsadogenic potential that occurs in very rare cases under specific
conditions in man. It appears difficult to mimic the different conditions that may be
involved in the initiation of Tdp in man. On the contrary, rare, poorly understood
side effects occur with many highly effective drugs and the withdrawal of these
medications from the market would probably harm more patients than it would
help. Our partial understanding of the mechanisms underlying Tdp is a two-edged
sword. On the one hand, drug safety has been improved: we are unlikely to see more
new drugs that unexpectedly result in a high risk of Tdp after they have reached the
market. On the other hand, as the molecular markers of risk for this and other
unusual actions of drugs are elucidated, there is a great risk of paralyzing the drug
development process in what is probably a fruitless effort to develop drugs that are
entirely devoid of adverse effects.
8 Summary
After the discovery of role of voltage-gated potassium channels particularly hERG
channels in the QT interval, there is no doubt that the level of awareness and
understanding of the problems of drug-induced QT interval prolongation has
progressed tremendously over last decade. ICH S7A, S7B and E-14 guidelines
have been framed to avoid reaching any drug to the market, which has the potential
to cause QT prolongation and ventricular arrthymia. We hope that ongoing rapid
genetic advances will allow populations at higher risk to be identified, so that
detection of risk becomes a practical means of screening. Hence, together with
regulatory authorities, the pharmaceutical industry needs to identify the criteria
needed to demonstrate the predictive value of new tests in such a way as to mitigate
the need for a clinical assessment of Tdp potential.