Cardiac Toxicity Testing
Two new studies offer perspective on CiPA.
As the field moves closer to implementation of the Comprehensive in vitro Proarrhythmia Assay (CiPA), two new perspectives are offered by Charles River scientists regarding this paradigm shift in cardiac toxicity testing.
A paper appearing July 13 reviews the rationale, progress and challenges for the CiPA initiative if this new paradigm is to replace existing practice and lead to improved, widely accepted cardiac safety testing guidelines. Carlos Obejero-Paz, and James Kramer, Principal Scientists at ChanTest Discovery Services, Charles River—which has been at the forefront of CiPA—were among the 20 authors of the perspective published in the Journal of Biomolecular Screening. The authors include many of the leading voices from industry and the US Food and Drug Administration working on defining CiPA.
The CiPA initiative came about after the realization that the current cardiac toxicity testing paradigm is too conservative, keeping potentially beneficial drugs off the market and, simultaneously, from patients who need them. At the same time, current methods are relatively poor predictors of drug-induced cardiac arrhythmias. With cardiovascular side effects an ever-pressing concern in drug safety, interest is growing in ion channel assays and in silico modeling, two methods that will augment though not likely alter current in vivo practice.
A second article appearing July 6 in the Journal of Pharmacological and Toxicological Methodsprovides its own perspective on the status of activities designed to assess the intrinsic value and reliability of CiPA. Co-authors of the paper include Icilio Cavero and Henry Holzgrefe, experts in cardiac electrophysiological safety of drugs, whose insights on CiPA have been the focus of a previous blog. Henry Holzgrefe is a safety pharmacology consultant for Charles River. An overriding theme in their current paper is the need to keep safety pharmacologists in the loop on CiPA.
In this manuscript, the authors noted that their assessment was limited to publicly available information presented at a recent CiPA Working Group. One of the points they raise relates to the CiPA component employing human stem cell-derived cardiomyocytes (hSC-CMs), which they said still await satisfactory resolution. The authors have lingering concerns that due to the variability in hSC-CM assay conditions, we may see a lot of "drift" among laboratories conducting the tests. However, they also acknowledge that robust experimental evidence has demonstrated that hSC-CMs can correctly identify numerous proarrhythmic drugs, which from a "functional point of view" provides some of the sought information. This may be fully satisfactory when additional experimental data become available, they said.
How to cite:
McEnery, Regina. Cardiac Toxicity Testing. Eureka blog. August 06, 2015. Available: https://eureka.criver.com/cardiac-toxicity-testing/