hERG in vitro interchange factors—development and verification

Abstract

Literature data analysis shows that the hERG interactions experiments carried out in different conditions with use of different in vitro systems for the same substance can result with different IC₅₀ values. One of the initial components of the proposed drug development supporting system is a set of extrapolation factors enabling the unrestricted choice of some elements of the experimental procedure without resultin significant depreciation. Therefore the main objective of this work was to develop the extrapolation factors allowing inter-system (HEK, CHO, XO) and inter-temperature (room and physiological) IC₅₀ values comparison based on the collected and analyzed hERG IC₅₀ data. The efficiency of the obtained factors was then verified in comparison with the native HEK IC₅₀ values at the physiological temperature. Low values of all the error estimates for the proposed factors evidence their good predictive value which, in turn, ground their application during drug candidates’ cardiotoxic risk evaluation or further in silico modeling. Utilization of the proposed factors during drug development process allows a more flexible choice of experimental model to exploit in the electrophysiological investigations, as well as makes it possible to experiment in ambient temperature, which is more convenient. The factors also facilitate data comparisons and allow one to draw reasonable conclusions for further extrapolation.

Keywords::

• Extrapolation factor
• hERG
• IC50
• cardiotoxicity
• drug development

Acknowledgments

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.