Table 3.
Do we have a mechanistic understanding of the liabilities?
| Tissue | Toxicity | Do we have a mechanistic understanding of the toxicity? |
|---|---|---|
| Heart | Proarrhythmic potential | For some but not all arrhythmias our knowledge is limited to QT and not to how arrhythmias translate to TdP. |
| Broad profiling of drugs against cardiac ion channels, action potential morphology on isolated tissues (e.g. Purkinje fibre, isolated hearts) and also ECG morphology are all available methods. | ||
| Have not been successful at converting mechanistic understanding in to new, regulatory accepted, biomarkers. | ||
| The contribution of genetics to the problem must also be considered. | ||
| Often when compound development is stopped due to proarrhythmic potential the exact mechanism is not completely known. | ||
| Myocardial ischaemia | Ischaemia can occur from increased oxygen demand and/or reduced supply and both of these have been studied non-clinically, for example, changes in vascular tone/coronary blood flow as well as cardiac function (heart rate and contractility). | |
| Myocardial necrosis | Knowledge of mechanisms is limited. | |
| Heart failure | Generally no, however, effects on cardiac contractility can be measured, but understanding the mechanisms that can change contractility is limited at the cellular level. | |
| Coronary artery disorders | Pharmacological mechanisms that can cause coronary artery constriction are well defined although the effects on endothelial function are less clear. | |
| Cardiac valve disorders | Only in some rare cases do we have an understanding of mechanisms but in general we have a poor understanding of drug effects on valve function. | |
| Pericardial disorders | Some inflammatory mechanisms can cause pericardial damage. | |
| Endocardial disorders | Some inflammatory mechanisms can cause endocardial damage. | |
| Vessel | Hypo/hypertension | Classical pharmacological mechanisms that affect vascular tone are well defined. However, others are not well defined. |
| Complex multifactorial control of BP often confounds identification of a specific mechanism. Some examples where site of action understood (e.g. vascular resistance and/or cardiac output change) centrally versus peripherally mediated and the role of some receptors is understood. | ||
| Vascular disorders | Causes are not well defined. | |
| Arteriosclerosis/stenosis | Changes in lipids and other factors are defined, but impact of inflammatory mechanisms is less clear. | |
| Vascular insufficiency | Causes are not well defined. | |
| Necrosis | Causes are not well defined. | |
| Vascular inflammation | Causes are not well defined. | |
| Blood | Embolism and thrombosis | Causes are not well defined. |
| Vascular haemorrhagic disorders | Causes are not well defined. | |
| Coagulation | Causes are not well defined. | |
| Aggregation | Causes are well defined. |
TdP, Torsades de Pointes; ECG, electrocardiogram; BP, blood pressure.