- The drug-induced long QT syndrome: basic pharmacology and
pharmacoepidemiology
- Pharmacology of the digestive system (research projects
focused especially on the enteric nervous
system)
1) THE DRUG-INDUCED LONG QT SYNDROME (http://cordis.europa.eu/result/rcn/53249_en.html)
Background : in the past decade, several drugs
have been withdrawn for safety issues related to their unwanted
interference with hERG channels leading to QT prolongation (which
is an important risk factor for occurrence of potentially fatal
cardiac arrhythmias). Thus, the issue of hERG liability is of great
interest both for drug developers and regulatory agencies. During
preclinical drug testing, different models are available to
investigate on the risk of QT interval prolongation by drugs (in
vitro and in vivo) and to allow early discontinuation of
the process for molecules with proarrhythmic potential, but none
per se is sufficiently predictive and costs are high. In
addition, during clinical trials, a too limited number of patients
is usually enrolled to obtain information on the actual risk of QT
prolongation. At present, estimates are that as many as 60% of new
molecular entities developed as potential therapeutic agents, when
assayed for hERG blocking liability, test positive and are thus
abandoned early in development. Thus, there is an urgent need for a
multidisciplinary approach to solve this problem.
Aims : the global aim is to develop methods for
early prediction of hERG liability and K+ channel blockade through
a network of scientists, which will include medicinal chemists,
experts in molecular and structural biology, experts in
pharmacology, clinical pharmacology, pharmacoepidemiology,
pharmacogenetics and biostatisticians. The specific aim of the
start-up phase is threefold: 1) to develop in silico models
of hERG blockade as a means for early prediction of hERG
liability; 2) to implement a pharmacoepidemiological network to
quantify the exposure to QT prolonging drugs, using prescription
data, and to quantify the incidence of drug-induced cardiac
arrhythmia by observational studies; 3) to develop a screening
protocol to identify genetic variants in cardiac ion channel genes
implicated in drug-induced QT prolongation.
Research group and integration of
competences: the project will be carried out by
several subunits with complementary, internationally
recognized scientific expertise and promote an international
collaboration addressing one of the topics of the European
Innovative Medicines Initiative Strategic Research Agenda. The
project has been carefully designed to ensure maximum coordination
and integration of the activities, reduce overlapping and optimise
the use of human resources.
Work plan and expected results of the start-up
phase: the work plan is divided into 3 macro work
packages, each carried out by one Subunit. The activities of the
Molecular Modeling Subunit will include both the development of
in silico models and the definition of computational
protocols for early prediction of hERG liability. The Clinical
Pharmacology/Pharmacoepidemiology Subunit will characterize the
risk of drug-induced QT prolongation in the population. The
Pharmacogenetics subunit will develop a screening protocol to
identify genetic variants in cardiac ion channel genes implicated
in drug-induced QT prolongation, in order to characterize the
spectrum and frequency of cardiac ion channel genes variants in the
population. The integration of the activities of the Molecular
Modeling Subunit with those of the other Subunits will be realized
by: a) considering the drugs identified by the Pharmacoepidemiology
Subunit as responsible of QT adverse events for an in depth in
silico study aimed at defining their binding mode to hERG; b)
considering polymorphisms identified by the Pharmacogenetics
Subunit in genes associated with the risk of drug-induced QT
prolongation for an in silico study of their possible role
in the variation of structural and/or functional properties of the
channel.
Possible technological, therapeutic and economic
advantages in the mid to long term: methods to obtain
safer new drugs would represent an advantage per se. Specifically,
using in silico methods to pursue this goal allows to
contain the high costs inherent to in vitro and in
vivo experiments. In addition, comparative evaluation of
classes of marketed drugs as regards their ability to prolong the
QT interval by pharmacoepidemiological studies allows a
re-appraisal of their risk-benefit balance. Defining the genetic
variability in cardiac ion channel genes in the Italian population
lays the foundation for the identification of disease-associated
variants and the development of a genetic test for early prediction
of drug-induced QT prolongation. The project will probably result
in guidelines for safer use of medicines in patients.
Innovative contribution: the urgent,
presently unmet need for early detection of hERG liability and
pharmacoepidemiology / pharmacovigilance of QT prolonging drugs is
a strong motivation for proposing this project as one of the means
to overcome an important bottleneck in drug development and also
promote safer use of medicines in patients. The particular,
multidisciplinary nature of our approach (development of a drug
design strategy based on the strong integration of
pharmacogenetics, pharmacoepidemiology, and molecular modelling) is
also innovative.
2) PHARMACOLOGY OF THE ENTERIC NERVOUS
SYSTEM
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