New Rapid Throughput Method Determines the Risk of Drug Cardiotoxicity

Cardiotoxicity is the reason why roughly one third of new pharmaceuticals are withdrawn from the market and why many compounds fail in late-stage clinical testing. To date, however, there has not been a rapid and accurate method for assaying the cardiotoxicity of potential drug candidates.

In the current study, which was published in the June 20, 2011, online edition of the journal Toxicological Sciences, investigators at Roche (Nutley, NJ, USA) described a high-throughput functional assay employing a monolayer of beating human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The assay system was based on the Roche xCELLigence Cardio Instrument. This instrument used 96-well plates with interdigitated electrode arrays to assess impedance, and the rhythmic, synchronous contractions of the iPSC-CMs were detected.

The xCELLigence Cardio System is powered by proprietary software and it employs 96-well E-plates to measure electronic cell impedance using sensor electrodes. Computer-controlled signal generation, automatic frequency scanning, and a measurement rate of 12.9 milliseconds per 96-well plate, enable high-speed, precise detection of changes in cardiac cell behavior.

Treatment of iPSC-CMs with 28 different compounds with known cardiac effects resulted in compound-specific changes in the beat rate and/or the amplitude of the impedance measurement. Changes in impedance for the compounds tested were comparable to the results from a related technology, electric field potential assessment obtained from microelectrode arrays (MEA). Using the results from the set of compounds, an index of drug-induced arrhythmias was calculated, enabling the determination of a drug's proarrhythmic potential.

“We found that measuring impedance provides a rapid means of interrogating a drug’s deleterious effect on human cardiac function, and not only helps us in early discovery safety assessment, but opens up new opportunities for investigating, cardiac biology, cell signaling, and disease pathogenesis,” said senior author Dr. Kyle Kolaja, director of the early and investigative safety, nonclinical safety, department at Roche. “More importantly, human pluripotent stem cell-based predictive toxicity assays will help researchers predict potential safety issues of promising drug candidates early in the development process and provide insight into the mechanisms of drug-induced organ toxicity.”

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