Cardiotoxicity is one of the leading causes of failure during drug development and also, more worrying, after marketing approval. Withdrawal due to cardiotoxicity has increased from 5.1 to 33%, including compounds to treat cardiovascular problems as well as drugs not intended to affect the heart such as antihistamines. Current used strategy to screen for adverse contractility effects involves a combination of preclinical in vitro pharmacological profiling, cardiomyocyte assays and in vivo cardiovascular (CVS) studies, and uses a variety of animal species (rats, mice, rabbits, guinea-pigs, dogs, pigs and non-human primates).
In spite of the variety of animal methods for preclinical screening for drug safety, 20-50% of all advanced candidates have to be abandoned due to adverse outcomes, even late in the drug development process.
The main aim is to accelerate the uptake of human-based in silico methodologies for evaluation of cardiac drug safety and efficacy in industry, regulatory and clinical settings.
The specific objectives include:
1) Review, collation and implementation of a comprehensive database of human electrophysiology and contractility in silico multiscale mechanistic models for specific cardiac disease conditions.
2) Development and qualification of in silico human models for the prediction of adverse outcomes in human cardiac electrophysiology and contractility for specific disease conditions, based on existing models, and calibration with in vivo and ex situ recordings.
3) Evaluation studies to compare in silico human-based predictions to clinical outcomes, current animal methods, and in vitro methods including stem cell derived cardiomyocytes.
4) Workshops and dissemination activities to identify and overcome barriers for the uptake of in silico methods in industrial, clinical and regulatory settings.
Project membership involves key partners across 11 countries who will raise the profile of in silico human models for the 3Rs.
Tomek J, Hao G, Tomková M, Carr C, Lewis A, Paterson DJ, Rodriguez B, Herring N, Bub G (2019). β-Adrenergic Receptor Stimulation and Alternans in the Border Zone of a Healed Infarct: An ex vivo Study and Computational Investigation of Arrhythmogenesis. Frontiers in Physiology 10: 350. doi:10.3389/fphys.2019.00350
Zhou X, Bueno-Orovio A, Schilling RJ, Kirkby C, Denning C, Rajamohan D, Burrage K, Tinker A, Rodriguez B, Harmer S (2019). Investigating the complex arrhythmic phenotype caused by the gain-of-function mutation KCNQ1-G229D. Frontiers in Physiology 10: 259. doi:10.3389/fphys.2019.00259
Mincholé A, Rodriguez B (2019). Artificial intelligence for the electrocardiogram. Nature Medicine 25: 22-23.
Passini E, Britton OJ, Lu HR, Rohrbacher J, Hermans AN, Gallacher DJ, Greig RJH, Bueno-Orovio A and Rodriguez B (2017). Human in silico drug trials demonstrate higher accuracy than animal models in predicting clinical pro-arrhythmic cardiotoxicity. Frontiers in Physiology 8: 668. doi:10.3389/fphys.2017.00668
Britton OJ, Bueno-Orovio A, Virág L, Varró A, Rodriguez B (2017). The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study. Frontiers in Physiology 8: 278. doi:10.3389/fphys.2017.00278
Britton OJ, Abi-Gerges N, Page G, Ghetti A, Miller PE, Rodriguez B (2017). Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine, and Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Models Incorporating Inter-Individual Action Potential Variability. Frontiers in Physiology 8: 597. doi:10.3389/fphys.2017.00597
Paci M, Passini E, Severi S, Hyttinen J, Rodriguez B (2017). Phenotypic variability in LQT3 human induced pluripotent stem cell-derived cardiomyocytes and their response to antiarrhythmic pharmacologic therapy: An in silico approach. Heart Rhythm 14: 1704. doi:10.1016/j.hrthm.2017.07.026
Principal investigatorProfessor Blanca Rodriguez
InstitutionUniversity of Oxford
Co-InvestigatorProfessor Andrew Tinker
Professor Pier Lambiase
Dr Alfonso Bueno Orovio