Nonclinical Cardiosafety Assays in Early Drug Development

Nonclinical Cardiosafety Assays in Early Drug Development 

Nondinical assessment of cardiac safety must be performed for a compound to qualify to be submitted to the health authorities to begin studies in man. For this purpose the regulatory bodies require that the cardiosafety assays should follow the principles of GLP wherever possible. The following assays/technologies are frequently used to predict potential clinical QT liability. 

A next-level assay is usually an isolated heart/cardiac tissue preparation. The canine Purkinje fiber assay (GLP) measures several action potential parameters, like resting membrane potential, upstroke velocity, action potential duration and shape, but also if a drug acts reverse-use dependently [72]. Based on changes of the action potential shape it is possible to conclude which ion channels are modulated (e.g., L-type calcium channel block would abolish the plateau phase). The papillary muscle assay (e.g., guinea pigs) determines similar parameters [73]. 

Additionally, the isolated heart can be used to measure chronotropic or inotropic effects. There are several additional ex vivo assays like the sinoatrial node preparation [76], left ventricular wedge preparation [77] available which address specific questions. All of the ex vivo studies mentioned above with the 

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