Cardiovascular disease is one of the leading causes of death worldwide at present. Despite the fact that investment in drug development has skyrocketed, there has been a decline in the number of approved drugs.
Cardiotoxicity can occur in late-stage clinical development and the early and efficient assessment of cardiac safety liabilities is crucial to confidently develop new drugs.
Assessment of drug-induced proarrhythmic risk and cardiac dysfunction at multiple levels is critical to modern cardiac safety screening.
Safe, reliable, economical preclinical assays to screen for effective drug candidates in early stages are essential. Aurora Biomed offers a cardiac safety assay service with an integrative approach to various functional assays for compound screening.
Cardiac safety and function assays
Drug-testing models used over the past decade involve a risk of high costs and unnecessary compound attrition, especially when comprehensive QT studies are conducted later in drug development.
Aurora Biomed provides predictable drug-testing models, such as a clinically-relevant rabbit Torsades de Pointes (TdP) model, to assess compound effects on ECG intervals and their proarrhythmic and anti-arrhythmic potential.
It also offers a unique system to investigate the details of cellular mechanisms of drug-induced positive or negative inotropy. A preparation of physiologically relevant rabbit whole-ventricle Purkinje fibers is available to test drug effect on action potential duration.
Why cardiac safety screening is difficult
The cardiovascular system, with its interdependence of blood vessels, blood constituents and circulation, as well as nervous and renal systems, is complex to model.
Many possible signaling pathways involved in normal function and pathogenesis make it a challenge to track drug interactions and limit the ability to make predictions about the safety and effectiveness of a drug.
While up to 70% of human toxicity may be apparent in the preclinical stage, more subtle, higher risk cardiovascular events may only emerge when drugs are given to humans in larger populations and over longer periods of time.
Current preclinical screening assays
Current preclinical screening assays involve both in vitro and in vivo models to detect toxicity, which could lead to heart failure and proarrhythmia. Non-specific, simple assays for early screening can lead to unjustifiably eliminating new drug entities due to false-positive findings.
The risk is increased by the different effects of compounds in humans and animals. The attrition rates in Phase 11 and Phase 111 development stages have been reported to be as high as 80%. Besides, some drugs have to be withdrawn after approval due to cardiotoxicity.
Comprehensive multi-parametric approaches
There are three broad categories for experiments: in vivo, in vitro and in silico studies and each study type has its advantages and disadvantages.
Tissue and bioengineering communities have been making extensive efforts to develop better in vitro and in silico models. This allows for more clinically and physiologically relevant results.
In vitro refers to studies done in a test tube rather than in a human or animal, whereas in vivo studies are done inside an organism.
In silico modeling involves the development of computer models to model physiologic or pharmacologic processes and logically extends in vitro experimentation.
Human-based engineered cardiovascular platforms have emerged and are beginning to revolutionize preclinical cardiac regulatory assessments. This paradigm shift has come about due to factors such as an ever-increasing knowledge about the basic molecular and cellular pathways underlying cardiovascular diseases, high-throughput screening systems and in silico models that can take into account the complexity of physiological functions.
The in vitro and in silico approaches are being used to complement preclinical in-vivo assessments. They will help to improve the various decision-making steps in the discovery and development of new drugs.