Current challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report

“…In some cases patients have been at risk. Overall it has cost the biopharmaceutical industry billions of dollars and hindered the delivery of new medicines to patients (Piccini et al, 2009). Thus there is a significant issue and one which requires the focus and close collaboration of nonclinical and clinical scientists from biopharma, contract research organizations, academia and regulatory agencies to address.…”

“…Predicting drug-induced QT prolongation and torsade de pointes in vitro and in vivo Dr Matt Skinner, AstraZeneca, UK Several drugs were withdrawn from the market, particularly between 1991 and 2003, due to an association with a rare but lifethreatening arrhythmia, torsade de pointes (TdP; Piccini et al, 2009). Drugs associated with TdP generally cause prolongation of the QT interval on the electrocardiogram and this has been adopted as a biomarker-albeit an imperfect one-for TdP (Piccini et al, 2009). By far the most common molecular mechanism by which a drug may prolong the QT interval is the inhibition of a repolarizing K + current (IKr) in ventricular myocytes; the alpha subunit of the channel responsible for IKr is encoded by the human ether-à-go-go-related gene (hERG).…”

Effects of tyrosine kinase inhibitors on rat isolated heart function and protein biomarkers indicative of toxicity

“…Issues with current preclinical studies include insufficient testing with truly informative, translatable models and biomarkers that will not only predict cardiovascular safety issues but also elucidate potential affected pathways before the drug reaches clinical testing (Laverty et al, 2011;Piccini et al, 2009). There has been a great deal of debate as to what assays and what biomarkers would fit the description of predictive, translatable, and cost effective in the long term.…”

Towards engineering integrated cardiac organoids: beating recorded

“…Among all, the cardiac organoids have attracted increasing attention due to their critical roles in toxicology; for example, it is estimated that cardiotoxicity represents a major side effect of systemic drug toxicityin the past 40 years 19% of drug recalls were likely due to cardiotoxicity (20).…”