Combining in vitro methods with in silico prediction is a powerful tool in predicting clinical outcomes in drug development. Applying this methodology to cardiotoxicity assessment is an important component of the new CiPA paradigm.
The In Silico Working Group are evaluating and extending the O’Hara-Rudy model of the human ventricular myocyte because it provides a more thorough and robust assessment of ion channel pharmacology and the risk in the clinic of Torsades de Pointes compared with other cardiotoxicity models. The extensive research and validation that went into creating the O’Hara-Rudy model was first published in 2011 and expanded upon previous models to include many essential physiological components that can contribute to cardiotoxic risk, including;
- CDI vs VDI inactivation of ICaL
- Kinetics of
- AP repolarization rate from 30% to 90% repolarisation
- APD at all physiological pacing rates with/without block of major currents
- APD restitution with/without block of delayed rectifier currents
- Transmural heterogeneity causing upright pseudo-ECG T-wave
- Early afterdepolarisation (EADs)
- Effects of CaMK
- AP and Ca2+ transient alternans
The In Silico Working Group found that “IKr was the only current likely to cause EADs when blocked (requiring ~87% block) and ICaL and INa-late were the currents most likely to modify (attenuate) these effects.” By incorporating state-dependence of the block to the IKr model, the Group successfully reproduced EADs in concordance with experimental results. In light of these positive indications, further exploration of in silico models are on hold until a complete set of ion channel data collected using standard protocols is presented.