Preclinical Cardiac Safety Assessment??of Drugs

Abstract

The heart is a frequent site of toxicity of pharmaceutical compounds in humans, and when developing a new drug it is critical to conduct a thorough preclinical evaluation of its possible adverse effects on cardiac structure and function. Changes in cardiac morphology such as myocardial necrosis, hypertrophy or valvulopathy are assessed in regulatory toxicity studies in laboratory animals, although specific models may be needed for a more accurate detection of the risk. The potential proarrhythmic risk of new drugs is a major subject of concern and needs to be fully addressed before treatment of volunteers or patients takes place. In vitro assays are conducted to determine the effects on cardiac ion channels, in particular I(Kr) potassium channel antagonism. Prolongation of the QT interval is assessed in vivo, generally in telemetered dogs. Together, these two tests are considered to detect most arrhythmic drugs. The results of this core battery can be refined by additional studies, in particular assays on isolated cardiac tissues determining changes in cardiac action potential duration, shape and variability over time. Triggering of arrhythmia is assessed in hypokalaemic dogs with artificially created bradycardia, or in vitro in isolated whole hearts. The proarrhythmic risk of the new compound is then evaluated by integrating the results of these different tests. Drug adverse effects on cardiac electrophysiological function, in particular impulse formation and conduction, are evaluated through changes in ECG, generally recorded in dogs, pigs or monkeys. Changes in cardiac contractility occurring either as a primary effect of the drug on cardiac function or as a consequence of cardiac lesions should also be carefully assessed. In telemetered or anaesthetised animals, cardiac contractility is evaluated by measurement of left ventricular pressure and its first derivative over time. Echocardiography allows non-invasive measurement of drug-induced changes in ventricular wall movements and cardiac haemodynamics indicative of effects on contractility. In conclusion, a reliable and accurate evaluation of the cardiac safety of a new pharmaceutical agent is based on the results of in vitro tests, with overall moderate to high throughput, and in vivo experiments assessing the effects of the drug on the heart in its physiological environment. The specific sensitivities of the animals used in these assays to cardiac adverse effects should also be considered. The final evaluation of the cardiac risk is therefore based on an integrated analysis of the results from a battery of tests.

Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: A tool for cardiac safety assessment

“…While a number of the withdrawn drugs had been shown to directly interfere with the hERG channel, it has been since shown that multiple ionic currents can influence hERG current block and furthermore hERG block alone sometimes does not provide a meaningful indication of QT prolongation or for that matter TdP. Furthermore, measurement of QT prolongation itself was shown to be highly sensitive for TdP, but not specific Hanton, 2007;Hoffmann & Warner, 2006). The emphasis on hERG in the non-clinical part of the guideline has had the unintended effect of substantially increasing the attrition rate of potentially promising compounds in development.…”

Should Cardiosafety be Ruled by hERG Inhibition? Early Testing Scenarios and Integrated Risk Assessment

“…Adverse drug effects on cardiac electrophysiological function, in particular impulse formation and conduction, are usually evaluated through changes in ECG, generally recorded in dogs, pigs or monkeys. TdP-related arrhythmias are detected very seldom in healthy dogs or monkeys but the triggering of arrhythmia could be investigated for example under hypokalemic conditions with artificially created bradycardia [4]. Adverse drug effects on cardiac electrophysiological function, in particular impulse formation and conduction, are usually evaluated through changes in ECG, generally recorded in dogs, pigs or monkeys.…”

“…Although the hERG channel has been shown to be the most significant of the risk factors that cause LQT, the full mechanism of TdP arrhythmia is more complex [13,15] and the range of relevant biological targets linked with other cardiac toxicities is much broader [4]. Other ion channels involved in regulating cardiac action potential are also known to cause cardiotoxicity.…”

“…In addition, other target classes such as kinases and GPCRs, have also been linked to human cardiotoxicity, and these are reviewed in the literature [4,16,17] and in another chapter.…”

Data-driven prediction of adverse drug reactions induced by drug-drug interactions

“…To alleviate this problem, ADRs caused by a single candidate drug are closely monitored and investigated during the drug development and approval process [2]. For instance, drug candidates are routinely tested in many in vitro and in vivo assays to predict their toxicity to humans [3]. Similarly, subsequent clinical trials usually focus on a single drug and its therapeutic effect against a particular disease or condition.…”