Biomedical Engineering Reference
In-Depth Information
associated with
Tdp
prolong the QT interval, though it should be noted that not all
drugs known to prolong QT interval have been connected with
Tdp
. Although a
variety of
in vitro
and
in vivo
experimental models are available for assessing the
QT prolongation and proarrhythmic potential of drug candidate, no single preclini-
cal model has been proven to be a predictive surrogate for human heart, that is
clinical exposure. Recognizing this need, pharmaceutical regulatory agencies
worldwide together with industry and academic scientists have developed guidance
urging an integration of several assays in hope that their combination will provide a
superior measure of true proarrhythmic risk. There are two documents developed
by the working group under ICH. One guideline is dealing with the non-clinical
strategy and another with clinical approach. Both recognize that the field of drug-
induced alterations in ventricular repolarization and proarrhythmia will undergo
changes as researchers are continuously gathering data, which in turn should adjust
the guidelines [
127
,
128
].
5.1 Preclinical Guidelines
1. Safety Pharmacology Studies for Human Pharmaceuticals (ICH S7A) ICH S7A
describes the “core battery” of methods used to characterize the safety pharma-
cology profile of a compound. The goal of the ICH S7A guideline is to describe
studies designed to assess the effects of drug molecule on vital physiological
functions prior to first testing in man. The undone business of ICH S7A guide-
line, namely, the description of studies to assess the proarrhythmic potential of
drugs through the prolongation of repolarization, was left for a secondary
guideline, ICH S7B [
129
].
2. The Non-Clinical Evaluation of Potential for Delayed Ventricular Repolariza-
tion (QT Interval Prolongation) by Human Pharmaceuticals (ICH S7B). Unlike
ICH S7A, ICH S7B heralds a new era for pharmaceutical industry since it now
sets out how to address safety concerns of a new chemical entity (NCE), in
relation to adverse reactions on ventricular repolarization, topic that has vexed
industry and regulatory authorities for many years. This guideline applies to
NCEs for human use and marketed pharmaceuticals when appropriate (e.g.,
when adverse clinical events, a new patient population, or new route of admin-
istration raises concerns not previously addressed). The objectives of the ICH
S7B studies are to identify the potential of a test substance and its metabolites to
delay ventricular repolarization and relate the extent of delayed ventricular
repolarization to the concentrations of a test substance and its metabolites.
The study results can be used to elucidate the mechanism of action and, when
considered with other information, estimate risk for delayed ventricular repolariza-
tion and QT interval prolongation in humans [
130
]. These guidelines describe a
non-clinical testing strategy for assessing the potential of a test substance to delay
ventricular repolarization. These guidelines also include information concerning
non-clinical assays and integrated risk assessments. The assessment of the effects of
