Cardiac Safety Assessment
Cardiac Safety Assessment refers to the evaluation of potential adverse effects of drugs or interventions on the cardiac system. This assessment is an essential component of preclinical and clinical drug development to identify and mitigate any risks of cardiac-related adverse events.
Cardiac Safety Assessment Testing Options Include
1.In vitro assay to determine binding of a compound to hERG
Assessing the interaction between a compound and the hERG potassium channel to evaluate the risk of QT interval prolongation and potential arrhythmias.
LeadQuest Biotech pioneers and champions cardiac safety research pertaining to hERG potassium channels. With over a decade of experience, we diligently track the latest advancements from ICH and FDA, continuously enhancing hERG detection and screening technologies to deliver precise data and expert interpretations to our clients.
The hERG potassium channel, a rapidly activating ion channel encoded by the human ether-a-go-go-related gene, plays a crucial role in phase 3 repolarization of myocardial action potential.
Blockage of the hERG channel by drugs can prolong cardiac repolarization, leading to long QT syndrome on ECG. In some cases, drug-induced delayed ventricular repolarization may result in a fatal arrhythmia known as torsade de pointes.
Statistics indicate that approximately 25-40% of lead compounds exhibit varying degrees of hERG-related toxicity, prompting the withdrawal of numerous drugs from the market due to the risk of QT interval prolongation.
In response, the International Council for Harmonization (ICH) has issued guideline S7B on preclinical studies of drug cardiotoxicity. Key experimental strategies include in vitro studies of IKr to assess drug effects on hERG, Nav1.5, and Cav1.2 ion channels in primary cardiomyocytes or recombinant cells, as well as in vivo QT detection.
2.Ion channel screening with patch clamp
Measuring the blockage of ion channels in cells to assess their impact on cardiac electrical activity and potential arrhythmogenic effects.
3.Tissue-based action potential recording using isolated Purkinje fibers
Recording the electrical activity of cardiac tissue to evaluate drug effects on cardiac action potential duration and potential proarrhythmic effects.
4.Organ-based ECG recording using Langendorff preparations
Assessing the electrocardiogram (ECG) of an isolated heart to evaluate drug-induced changes in cardiac electrical activity and potential arrhythmias.
5.Stem cell-induced differentiated cardiomyocyte action potential
Refers to the electrical activity of heart muscle cells generated from stem cells through a process of differentiation.
Arrhythmia Model
Cardiac repolarization toxicity (QT interval prolongation and torsade de pointes) is a serious and widespread adverse reaction, with one-third of the drugs withdrawn from the market due to drug-induced arrhythmias.
Inhibition of hERG potassium channels is a major cause of arrhythmic toxicity. hERG, as the main index for evaluating drug-induced arrhythmia toxicity, has serious problems in sensitivity and specificity, so in 2013, the FDA began to promote a comprehensive in vitro proarrhythmia assay (CiPA).
CiPA consists of four core components:
- Evaluation of multiple ion channels in the heart
- Computer virtual reconstruction of action potentials
- iPSC-induced differentiation cardiomyocyte model
- Clinical ECG evaluation.