Cardiac Liability Testing Solutions

Eurofins Discovery’s scientists have successfully developed and validated assays for assessing safety risk potential for patients with cardiac liability, with human induced pluripotent stem-cell cardiomyocyte assays. As the first Contract Research Organization to provide testing by automated electrophysiology, Eurofins Discovery has continued to expand on that expertise alongside advancements made in the field, with comprehensive assays for improved cardiac risk prediction.
 
Cardiovascular safety liabilities remain a major cause of attrition for lead candidates and investigational new drugs in a clinical and pre-clinical setting, including possible withdrawal of released medicines. As a result, it is essential to perform cardiac liability testing in comprehensive and physiologically relevant preclinical models to assess for potential cardiac liabilities early during the drug discovery process. Adult human-induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CMs) represent an excellent model for studying in vitro effects, because these cells express ion channels that underlie action potentials and exhibit electrophysiological and mechanical characteristics of native human cardiomyocytes.
 
In hiPSC-CMs, calcium (Ca²⁺) acts as an intracellular second messenger linking the electrochemical signals of the action potential to cardiomyocyte contraction: High levels of intracellular Ca²⁺ lead to contraction of the cardiomyocyte and low levels of intracellular Ca²⁺ lead to relaxation. Changes in the activity of the action potential-inducing ion channels will therefore result in a changed shape and duration of the intracellular Ca²⁺ transient. Consequently, the intracellular Ca²⁺ transient may be utilized as a surrogate marker to evaluate the effects of compounds on cardiac function.
 
Our experts have developed and validated a high-throughput assay in hiPSC-CMs using a Ca²⁺ sensitive dye and the FLIPR^® Penta High-Throughput Cellular Screening System to monitor intracellular Ca²⁺ oscillation in response to test compounds. This assay may be utilized to assess for the risk potential of test compound-induced delayed ventricular repolarization and QT interval prolongation in humans.

Assay applications include:

• Safety pharmacology
• Cardiotoxicity testing
• Discovery of novel cardiac drug targets
• Precursor to phenotypic screening

Validated Assay using FLIPR Screening System

Eurofins DiscoverX has developed and validated an assay in hiPSC-CMs to monitor intracellular Ca²⁺ transients in response to test compounds using the FLIPR Penta High-Throughput Cellular Screening System (see below).

A. Mean Peak Rate/Beats per minute (BPM)
B. Peak Spacing: Time (in seconds) between two peaks
C. CTD90: Calcium Transient Duration at 90% of decay following the peak amplitude (in seconds)