Foto del docente

Fabrizio De Ponti

Full Professor

Department of Medical and Surgical Sciences

Academic discipline: BIO/14 Pharmacology


Keywords: clinical pharmacology and rational prescribing drug safety drug-induced QT syndrome gastrointestinal pharmacology enteric nervous system animal models of human disease application of artificial intelligence in medicine and medical learning

- The drug-induced long QT syndrome: basic pharmacology and pharmacoepidemiology 

- Pharmacology of the digestive system (research projects focused especially on the enteric nervous system)


Background : in the past decade, several drugs have been withdrawn for safety issues related to their unwanted interference with hERG channels leading to QT prolongation (which is an important risk factor for occurrence of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.


See relevant publications in Google Scholar: Link