Multi-Well Engineered Heart Tissue for Drug Screening and Predictive Toxicology

Abstract

Drug development is timeand cost-intensive and, overall, inefficient. Only one out of an estimated 10.000 new chemical entities (NCEs) finally enters the market. The later the failure occurs, the higher are the costs. It is for this reason that preclinical development aims at identifying the potential for failure as early as possible and with high sensitivity. On the other hand, high sensitivity generally also means low specificity, suggesting that many potentially successful NCEs are currently excluded from further development. Common reasons for exclusion are adverse drug reactions (ADR). Among the various ADRs, cardiac toxicities and arrhythmias play an important role, because they represent about 21% of all ADRs (Lasser et al., 2002) and are frequently lethal. The single most important mechanism in this context is the prolongation of cardiac repolarization bearing a proarrhythmic potential. These interferences can be visualized by standard ECGs as a prolongation of the QT-interval. Such a prolongation is called “long QT-syndrome” (LQT-syndrome) and is associated with Torsade-de-Pointes (TdP) arrhythmias and sudden cardiac death. In the past, several prominent drugs had to be withdrawn from the market due to TdP in humans, e.g. astemizole, terfenadine, cisapride, sparfloxacin, grepafloxacin and recently clobutinol (Silomat). Moreover, numerous drugs are still on the market that are associated with the potential to cause LQT and TdP, including widely prescribed drugs such as the antibiotic erythromycin. Given the fatal consequences of LQT and TdP in healthy patients without any cardiac disposition, the regulatory bodies (FDA, EMEA and others) have decided some years ago to require testing for LQT to be an obligatory part of preclinical development of any NCE. Several tests have been developed and some of them are routinely used. The three major (but by far not exclusive) tests in the field are the HERG test, rabbit Purkinje fibers and telemetry in dogs. These tests have different advantages and disadvantages and are generally employed subsequently. The HERG test can be considered an obligatory test for all NCEs and it is unlikely that any company further develops a compound that showed major inhibitory activity in this test (of a single ion channel activity). However, examples exist of successful drugs on the market that are potent inhibitors of the HERG current without ever giving rise to TdP arrhythmia (e.g. verapamil, azithromycin). Thus, the predictive value of the HERG test is limited. Reasons lie, among others, in its inability to