Biomarkers
Biomarkers of cardiotoxicity Non-invasive or systemic biomarkers that can predict or track cardiotoxicity are greatly need- ed, both for clinical monitoring and as surrogate endpoints in drug development. Ideally, bio- markers of cardiotoxicity should be able to dis- tinguish myocardial from skeletal muscle or other tissue damage, be present in serum or plas- ma, and be translatable from animal to human studies. It remains unlikely that there will ever be a single biomarker that can predict all drug- induced cardiotoxicities, but rather an optimal panel of biomarkers will be developed as a mul- tiplex test for use in the laboratory and in the clinic. Selection of the appropriate biomarkers, time of sample collection and interpretation of test results will all be critical factors in go/no-go candidate decision making.
The QT interval is one of the oldest and most widely used safety biomarkers in drug develop- ment. There are also specific circulating molecular biomarkers that may be used to signal potential drug-induced cardiotoxicity. The cardiac troponins and natriuretic peptides may represent early and specific signals of cardiac damage or functional impairment – and could greatly complement QT interval in the cardiac screening of new com- pounds early in development.
QT interval
The QT interval remains one of the most widely used safety biomarkers in drug development. A great deal is known about the molecular mecha- nisms that link QT interval to clinical outcomes, namely cardiotoxicity. Ion channels present in car- diac cell membranes are responsible for generating the electrical currents that lead to cardiac muscle contraction, enabling the heart to pump blood. These currents have a distinct pattern of voltage change known as an action potential, which can be measured at the skin surface using an electrocar- diogram (ECG). The length of the interval between two well-defined points on the ECG – the QRS complex and the T wave (the QT interval) – is commonly measured to identify the cardiotoxicity potential of a drug (Figure 1). Deviation from a predictable ECG pattern signals potential cardiac problems such as the potentially fatal cardiac arrhythmia torsades de pointes (TdP). Ion chan- nels, such as the human Ether-à-go-go Related Gene (hERG), are the most likely molecular targets by which drugs prolong the QT interval. In the early 1990s, there was a significant increase in the number of TdP adverse events being reported in post-marketing data, which led
Drug Discovery World Summer 2011
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