hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 182

irrespective of the pre-clinical data, a thorough clinical ECG study will be required
at some point during development [ 56 , 139 ].

6.3 Electrophysiological Studies Using Mammalian Cell Lines

Some of the emerging methods involving channel proteins and isolated cells
include automated patch clamp, hERG assay under pathophysiological conditions,
pharmacodynamic interactions at the hERG channel, test for stereoselectivity,
expression of hERG protein on the cell surface and effects on other cardiac ion
channels can be good approaches to predict the risk of QT prolongation. Emerging
automated patch-clamp methodologies promise to greatly enhance screening effi-
ciency. It has the potential to become valuable high-throughput (HTP) screen
during lead identification/optimization. PD interactions at hERG channel may
involve binding at active or allosteric interactions. The effects can be synergistic
or antagonistic. Test for stereoselectivity can be considered if racemate of NCEs is
used. Effects on other cardiac ion channels can also be assessed if hERG block at
relevant concentrations does not translate into effects on action potential duration/
QT or if non- hERG effects on APD and ECG are seen [ 11 , 32 , 140 ].

6.4 In Vivo Methods

Beat-to-beat variability, T-wave morphology, effects on autonomic tone and intra-
cardiac accumulation and metabolism are some of the emerging foci of research
involving preclinical in vivo studies. Conscious anesthetized non-rodents are
increasingly being studied using parameters derived from in vitro proarrhythmia
indices. It is hoped that these models will give rise to better surrogate markers such
as beat-to-beat variability and T-wave morphology. The latter has the potential to
become a highly predictive for human torsadogenesis hence can be used for safety
margin calculation [ 124 , 141 ]. Effects on autonomic tone may be investigated on a
case by case basis, while intra-cardiac accumulation, transporters and metabolism
can be considered if effects on repolarization are unexpectedly seen at doses that
should have high enough safety margin according to hERG assay [ 13 , 142 , 143 ].

7 Strategies to Tackle QT Prolongation Associated with hERG

Inhibitors

Tdp is typically not seen during the development of a new drug until the filing of
IND (Investigational New Drug Approval), which includes testing in typically less
than 5,000 patients during clinical phase I-III. Following registration, evidence of