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 for adverse events and drug attrition is cardiovascular toxicity1, 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 (ICH) issued a guideline for the examination of new drug candidates in a series of in vitro and in vivo tests to assess their arrhythmogenic potential3. Inhibition of the delayed rectifier potassium current (IKr) 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 IKr or hERG, the potassium channel that underlies IKr4. The development of high-throughput automated methods to measure hERG currents in heterologous expression systems has fueled the emphasis of in vitro testing on IKr early in drug discovery and perhaps prevented the development of new medicines by discarding compounds prematurely.
- Received May 30, 2014.
- Accepted June 2, 2014.