Cardionomics: A new integrative approach for screening cardiotoxicity of drug candidates

Judith K. Gwathmey, Katya Tsaioun, Roger J. Hajjar

Research output: Contribution to journalReview article

Abstract

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be performed to rule out potential cardiac toxicity, many drugs have nevertheless entered the market only to be later withdrawn from the market owing to cardiac toxicity.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. Conclusion: 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safety issues before clinical launch can have an enormous cost for the pharmaceutical industry, when major drugs are withdrawn due to lawsuits as well as loss of time and resources.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.

Original languageEnglish (US)
Pages (from-to)647-660
Number of pages14
JournalExpert Opinion on Drug Metabolism and Toxicology
Volume5
Issue number6
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Keywords

  • Action potential
  • Adverse cardiac events
  • Antiarrhythmic drugs
  • Arrhythmia
  • Assays
  • Calcium transients
  • Electrophysiology excitation-contraction coupling
  • Idiopathic dilated cardiomyopathy
  • Ion channels
  • hERG

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint Dive into the research topics of 'Cardionomics: A new integrative approach for screening cardiotoxicity of drug candidates'. Together they form a unique fingerprint.

  • Cite this