Biomedical Engineering Reference
In-Depth Information
pharmaceuticals on ventricular repolarization and proarrhythmic risk is the subject
of active investigation. The ICH S7B guideline, in the primary non-clinical testing
strategy for assessing evidence of the risk of compounds to prolong the QT interval,
has recommended the use of an
in vitro
IKr assay that evaluates the effects on IKr or
the ionic current through a native or expressed IKr channel protein, such as that
encoded by
hERG
and an
in vivo
QT assay that measures indices of ventricular
repolarization, such as QT interval [
129
,
131
].
5.2 Clinical Guidelines
In 2005, the International Conference on Harmonization released a document ICH
E-14 concerning the clinical evaluation of QT and/or QTc interval prolongation and
proarrhythmic potential for non-antiarrhythmic drugs. The guideline calls for a
clinical thorough QT/QTc study (typically conducted in healthy volunteers), which
is intended to determine whether a drug has a threshold pharmacological effect on
cardiac repolarization, as detected by QT/QTc interval prolongation [
132
]. The ICH
E-14 recommendations are generally applicable not only to new drugs that have
systemic bioavailability but also to approved drugs when a new dose, route of
administration, or target population that may result in an increased risk is explored.
According to ICH E14 guideline, every drug should receive an extensive electro-
cardiographic evaluation in man. Although the guideline acknowledges the fact that
QT prolongation is a poor marker for proarrhythmic risk, it postulates that there is a
rough correlation between the mean degree of QT prolongation and the observed
clinical proarrhythmic events [
128
]. Furthermore, non-clinical and especially
proarrhythmic assays will be able to estimate whether concurrent observations of
non-clinical and clinical repolarization delay is likely to impose a risk of
Tdp
.This
also reflects the point that proarrhythmic conclusions should not be drawn from
neither preclinical nor clinical QT studies. The objective of the guideline is to offer
recommendations regarding the design, execution, analysis, and interpretation of a
clinical study to evaluate the potential of a drug to delay cardiac repolarization
[
129
,
133
].
6
hERG
Assay to Predict QT Prolongation
6.1
In Silico Methods
An alternative approach that can be applied during the earliest stages of the drug
design and discovery process is
in silico
prediction of
hERG
channel blockade, based
on pharmacophore models and knowledge of the drug-binding site of
hERG
channels. This approach is controversial because it has a significant potential for
