Cardionomics: a new integrative approach for screening cardiotoxicity of drug candidates.
BACKGROUND
Despite the FDA guidelines for studies to be performed to rule out potential cardiac toxicity, many drugs have nevertheless entered the market only to be later withdrawn from the market owing to cardiac toxicity. Cardiac toxicity may result from drugs causing impaired function or death of cardiomyocytes, valvular damage, myocardial ischemia and/or ventricular arrhythmias. Negative cardiovascular events have been implicated in 28% of drug withdrawals in the USA. The significance for patients, regulators and the pharmaceutical industry is immense.


OBJECTIVE
We address whether a more rigorous and integrative approach is needed for cardiovascular safety screening of all new drug candidates. Furthermore, we will present a cardionomics approach that looks at several in vitro and in vivo models that can be applied to all drugs independent of category, therapeutic area or class.


METHODS
We present examples of drugs demonstrating cardiac toxicity and provide an in-depth review of how calcium homeostasis may be a unifying theme in clinically observed cardiotoxic events. We introduce a cardionomics approach that detects clinical cardiac toxicity early in the drug discovery process, thus, preventing costly late attrition.


CONCLUSIONS
The consequences of a failure to detect potential cardiovascular safety issues before clinical launch can have an enormous cost for the pharmaceutical industry, when major drugs are withdrawn due to lawsuits as well as loss of time and resources. An integrated cardionomics approach may reduce the risk of drug withdrawals as a result of unexpected clinical cardiac safety issues.
Gwathmey
Judith K
JK
Division of Cardiology, Boston University Medical Center, Cambridge MA 02138, USA. jgwathmey@gwathmey.com
Tsaioun
Katya
K
Hajjar
Roger J
RJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control; D035843:Biomedical Research / Q000379:methods; D002317:Cardiovascular Agents / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage
D002317:Cardiovascular Agents; D004364:Pharmaceutical Preparations