For cardiac safety pharmacology in drug discovery programs, there is obviously more to consider than pure direct hERG channel blockade. Further molecular features that require attention include interactions with other cardiac ion channels, which can aggravate or alleviate the effects of direct IKr blockade. Also, the blocking effect on the hERG channel can depend on the stimulation frequency and the stimulation protocols used. Most simply, the Cmax of a drug on the hERG ion channel can be set in correlation to the free maximal plasma concentration. Based on a dataset of 100 drugs, a factor of 30–100 between these two values has previously been suggested to offer a potentially sufficient window of safety from arrhythmias induced by hERG channel blockade. Additional factors that influence the physiological impact of a drug's effect on IKr are tissue accumulation of a substance, as well as the reversibility of a blocking effect.
Other effects only arise at higher levels of organization, as found in cardiac tissue: action potential measurements in Purkinje fibers have been shown to predict the proarrhythmic risk of terodiline and also the relatively benign clinical cardiac profile of tolterodine. While both compounds are relatively potent hERG blockers, terodiline (in contrast to tolterodine) induces triangulation of the action potential, which is shown to be a valuable indicator of cardiac risk.[59,60]
Furthermore, the multilayered, electrophysiologically heterogeneous structure of ventricular tissue induces a transmural dispersion of repolarization. Assay systems to study such effects in vitro or ex vivo have been developed: Purkinje fiber and left ventricular wedge preparation[61,32] and the isolated (Langendorff) heart preparation. Using isolated heart preparations, effects on the transmural dispersion, in combination with the shape of the cardiac action potential, have been found to be much better markers for proarrhythmia than hERG channel blockade or the QT interval alone[60,62–64] – although such assessments as well as the corresponding data evaluations are technically and scientifically demanding, and experimental conditions have been shown to greatly influence the data, giving rise to discussions regarding the interlaboratory variability of data generated by these methods.[65–67] Another disadvantage of such preparations is that they rely on organ preparations from animal species. Consequently, these models introduce species differences into the safety pharmacology investigations. Recent in vivo investigations have convincingly demonstrated that the beat-to-beat variability of the QT interval (in humans)[68,69] and the beat-to-beat variability of repolarization (in dogs)[70,71] are reliable indicators of proarrhythmic risk. At least in the specific dog model, beat-to-beat variability of repolarization was shown to be more predictive of drug-induced TdP than the QT interval duration. Carefully designed and executed experiments using any of these models undoubtedly deliver highly valuable information on cardiac safety and reasons for potential arrhythmia but, owing to the drawbacks mentioned, these assays may not be indicated as routines in early drug discovery programs. While none of the existing or novel test systems appears suitable to replace patch clamp hERG channel tests, they do provide additional information to support informed decision making during the drug development process.
With an estimated 25–40% of all lead compounds demonstrating some liability towards the hERG ion channel, and nearly all compounds that have been withdrawn from the market owing to TdP being potent hERG channel inhibitors, the current emphasize on investigating compound-mediated hERG effects appears reasonable. However, particularly for valuable later-stage compounds, investigating compound effects on the cardiac ion channels beyond pure hERG channel blockade, and on the action potential beyond pure QT prolongation, delivers valuable information. These can help to unravel the mechanisms of potential TdP, and give medicinal chemists insight for reducing the liability of compounds. In addition, awareness of the induction of other proarrhythmic features, such as QT shortening, which can degenerate into life-threatening ventricular fibrillation, must be increased.
Expert Rev Clin Pharmacol. 2010;3(3):321-329. © 2010 Expert Reviews Ltd.
Cite this: Keeping the Rhythm: hERG and Beyond in Cardiovascular Safety Pharmacology - Medscape - May 01, 2010.