Thursday, 19 April 2018 07:04

Cardiotoxicity testing: stalling implementation of new methods Featured

In its first issue of a new series "Replacement of the Year", the German Animal Rights Organisation People for Animal Rights Germany (PARG) criticises the stalling implementation of new methods to replace animal organ consumption in cardiotoxicity testing.

Cardiotoxicity, the harmful effect of drugs on the heart, is the reason for about a third of all new drugs withdrawn from the market and for the end of many active ingredients in the late clinical development phase. The costs for drug development now amount to approximately 2.6 billion dollars over a production period of between 10 and 15 years.

Cardiotoxicity tests for drug research and development are defined in Directive S7B of the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The tests provide for a combination of animal testing and animal-free procedures.  Among other things, the regulation describes the hERG test, a test procedure on a calcium channel of the heart, from which it was assumed in the 90s that solely its inhibition seems to be the molecular mechanism of the cardiac arrhythmia caused by drugs. Meanwhile, however, it is known that The exclusive measurement of hERG can lead to incorrect results. A Prolongation of the action potential can be induced by both, a reduced inactivation of the inwardly directed Na+- or Ca2+ currents, increased activation of the Ca2+ current or inhibition of one or more of the outward K+-currents can result. Furthermore, heart tissue and whole hearts of rabbits are used, although scientists are increasingly critical of Langendorff's heart preparations because they cannot integrate pathological and pharmacological conditions into an autonomously functioning nervous system.


New broschure issues cardiotoxicity testing in drug development.
Photo: PARG.

In recent years, scientists have carried out state-of-the-art cardiotoxicity tests with human heart cells from stem cells on chip technologies. The methods are often used already in validation studies with the industry, however they are not mandatory.

With the CiPA Initiative (1), scientists of the United States together with other international researchers have developed a new testing strategy and integrated these new methods. However, their inclusion in the test regulations is being delayed. Meanwhile, the industry is still using the outdated tests (2). The rapid implementation of new test guidelines under incorporation of the new human-specific methods into the guidelines is demanded.

With its public relations work, the animal rights organisation wants to draw attention to these abuses and demands that rapid incorporation of the new human-specific methods into the guidelines.

1 Initiative Comprehensive In Vitro Proarrhythmia Assay (CiPA) der Food and Drug Administration.

2 Authier, S., Pugsley, M. K., Koerner, J. E., Fermini, B., Redfern, W. S., Valentin, J.-P., Vargas, H. M., Leishman, D. J., Correll, K. and Curtis, M. J. (2017). Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice. Journal of Pharmacological and Toxicological Methods 86, pp. 34–43.