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The Centre for Research and Innovation in Bioengineering (Ci2B) of the Universitat Politècnica de Valencia (UPV), in collaboration with the French company ExactCure, has developed a computational simulation methodology to assess the risk of different drugs inducing cardiac arrhythmias, specifically Torsade de Pointes, as a side effect.

The system, based on a combination of pharmacokinetic models - which simulate the distribution and elimination of drugs in the human body - and electrophysiological models - which simulate the electrical activity of the heart and how drugs alter it - provides valuable information on the complex interactions between drug effects, gender (male/female) and renal function, as well as testing and identifying the safe dose to administer from a cardiac point of view based on patient characteristics.

"Assessing the risk of causing Torsade de Pointes," says Jordi Llopis (Ci2B), first author of the study, "is one of the main challenges facing the pharmaceutical industry and regulatory agencies, both during the development of new drugs and in clinical practice, given the seriousness of the possible consequences, which include death.

"In this respect," he continues, "the study demonstrates the potential of in-silico pharmacokinetic and electrophysiological simulations to improve the assessment of the risk of drugs inducing cardiac arrhythmias.

Results

The study, conducted on a sample of 1,200 virtual patients, concluded that at identical drug doses, women with impaired renal function were more likely to develop cardiac arrhythmias than men in the same circumstances and men and women without poor renal function. These results suggest that women with impaired renal function may need either a lower drug dose or closer monitoring of their heart function.

It should also be noted that this research demonstrates the potential relevance of in-silico medicine (via computational simulation), which "offers the possibility of systematically and efficiently evaluating a wide range of factors, making it possible to optimise pharmacological therapies". Indeed, Llopis adds, "further research in this area may contribute to the development of personalised medicine approaches that ultimately lead to safer drug therapies for patients".

Current lines of research

The work, whose results have been published in the Computer Methods and Programs in Biomedicine journal, is part of the SimCardioTest project, funded by the European Union. Its main objective is to demonstrate the feasibility, efficacy and benefits of in-silico testing of drugs and cardiological devices, and its ultimate goal is to have a realistic 3D geometry to test it.

The Ci2B research group, supported by the Barcelona Supercomputing Centre, is also working on the evaluation of pharmacological safety in situations of cardiac ischaemia, developing strategies to assess the effectiveness of various drugs against heart failure and atrial fibrillation, the most common arrhythmia in the population, and collaborating with the Norwegian company Simula Research Laboratory to incorporate the mechanical aspect of the heart.

Reference: Llopis-Lorente, J., Baroudi, S., Koloskoff, K., Mora, M. T., Basset, M., Romero, L., ... & Trenor, B. (2023). Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity. Computer Methods and Programs in Biomedicine, 107860.