hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 163

proarrhythmic drugs are derived from epidemiological studies, anecdotal case
reports and clinical studies during drug development and post-marketing surveil-
lance. The awareness of drug-induced Tdp in last few years has resulted in increase
in the number of spontaneous reports. Nevertheless, the absolute total number
remains very low, although it has been suggested that the system of spontaneous
reporting under-reports the true incidence of serious adverse reactions by a factor of
at least 10 [ 48 ]. Between 1983 and December 1999, 761 cases of Tdp , of which 34
were fatal, were reported to the World Health Organization Drug Monitoring
Centre by the member states. WHO data provide an insight into the incidence of
Tdp on most commonly reported proarrhythmic drugs. However, such a reporting
system is undermined by the widely variable content and clinical information
between different countries and sources. It is also compounded by various factors
such as the patient's underlying disease, whether adverse drug reaction is well
known or has not been previously described and the amount of attention paid by the
medical community on a specific adverse drug reaction [ 49 , 50 ].

K + Channels as a Therapeutic Target

3 hERG

hERG potassium channels are essential for normal electrical activity in the heart.
Inherited mutations in the hERG gene cause long QT syndrome, a disorder that
predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be
induced by a blockage of hERG channels by a surprisingly diverse group of
drugs. This side effect is a common reason for drug failure in preclinical safety
trials. Insights gained from the crystal structures of other potassium channels have
helped our understanding of block of hERG channels and the mechanisms of gating
[ 51 ]. Many drugs have been withdrawn from the market and a large number of
promising compounds have been stopped during development due to suspected or
confirmed adverse events, including fatalities. Cardiac, hepatic and hematological
abnormalities are the major causes of withdrawal of drugs or restriction in their
labeling. Among these unintended effects, drug-induced arrhythmogenic death is
the most dramatic. The common cause of the withdrawal or restriction of drugs
produced delayed ventricular repolarization and the prolongation of QT interval
associated with fatal polymorphic ventricular tachycardia, or Tdp . A convergence
of data obtained from clinicians, basic electrophysiologists and geneticists who
have studied the congenital long QT syndrome (also characterized by Tdp ) has
resulted in some understanding of the mechanisms, whereby drugs may cause this
type of arrhythmia. Guidelines, which are still evolving, are aimed at predicting
whether a new drug carries this risk. Paradoxically, however, increased knowledge
has also illuminated the fact that the current predictors of this serious side effect
are imperfect, both for individual patients and for populations of patients who are
exposed to a given drug. Thus, although clinicians, members of regulatory bodies
and drug developers, may be able to predict that a given drug may carry some risk,
they can neither assess nor quantify it accurately [ 23 , 52 , 53 ].