Biological Simulation in the Industrial Laboratory: Predicting Cardiotoxic Potential of Drug Candidates from in vitro Data

Dean Bottino

The BioAnalyitics Group

Drug induced arrhythmia is a life-threatening condition that has been implicated in half of the safety-related withdrawals of drugs from the market since 1997.  It continues to be a problem for pharmaceutical companies, affecting every major drug class, resulting in late stage failures of drug candidates, unfavorable labeling and withdrawals of FDA approved products, wasted animal testing and loss of human lives, with a cost of hundreds of millions of dollars annually. 

We have addressed this problem with a combined laboratory and computer-based approach to the assessment of safety risk.  We will present a use-case to illustrate how we used biological simulation to provide timely decision-making information for a client’s drug candidates.  We will place particular emphasis on our application of parameter estimation and uncertainty analysis: (1) to quickly develop a new cardiac simulation model for the canine Purkinje fiber, (2) to reverse-engineer physiologically meaningful hypotheses that reconciled apparent contradictions between two of the customer’s cardiac safety assessment assay datasets, and (3) to modify the data requirements of our analysis to fit more readily into the customer’s safety assessment work flow in the future.