Is There a Need to Add Another Dimension (Time) to the Evaluation of the Arrhythmogenic Potential of New Drug Candidates In Vitro?

Most drug therapy regimens expose the human body to a foreign chemical for several hours to days and even years. Hence, before a new drug is approved by regulatory agencies, extensive safety studies are conducted to ensure that exposure to the drug will not cause undesirable effects in patients. A major cause of adverse events and drug attrition is cardiovascular toxicity.1,2 Drug developers have attempted to identify these issues earlier in medicine development to reduce risks to human volunteers in clinical trials and costs of pursuing the development of unsafe drugs. In 2005, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use issued a guideline for the examination of new drug candidates in a series of in vitro and in vivo tests to assess their arrhythmogenic potential.3 Inhibition of the delayed rectifier potassium current ( I Kr) in the heart has been linked to the majority of drug-induced arrhythmias. As a result, in vitro safety testing has been focused on acute drug effects on I Kr or hERG, the potassium channel that underlies I Kr.4 The development of high-throughput automated methods to measure hERG currents in heterologous expression systems has fueled the emphasis of in vitro testing on I Kr early in drug discovery and perhaps prevented the development of new medicines by discarding compounds prematurely. This testing paradigm has been challenged over the past several years with the realization that verapamil and a number of other drugs that inhibit I Kr at therapeutic concentrations do not cause arrhythmias in patients. Verapamil has compensatory effects on other cardiac ion channels such that action potential duration is …