Supporting an integrated QTc risk assessment using the hERG margin distributions for three positive control agents derived from multiple laboratories and on multiple occasions.

Background: Determination of a drug's potency in blocking the hERG channel is an established safety pharmacology study. Best practice guidelines have been published for reliable assessment of hERG potency. In addition, a set of plasma concentration and plasma protein binding fraction data were provided as denominators for margin calculations. The aims of the current analysis were five-fold: provide data allowing creation of consistent denominators for the hERG margin distributions of the key reference agents, explore the variation in hERG margins within and across laboratories, provide a hERG margin to 10 ms QTc prolongation based on several newer studies, provide information to use these analyses for reference purposes, and provide recommended hERG margin 'cut-off' values.

Methods: The analyses used 12 hERG IC 'best practice' data sets (for the 3 reference agents). A group of 5 data sets came from a single laboratory. The other 7 data sets were collected by 6 different laboratories.

Results: The denominator exposure distributions were consistent with the ICH E14/S7B Training Materials. The inter-occasion and inter-laboratory variability in hERG IC values were comparable. Inter-drug differences were most important in determining the pooled margin variability. The combined data provided a robust hERG margin reference based on best practice guidelines and consistent exposure denominators. The sensitivity of hERG margin thresholds were consistent with the sensitivity described over the course of the last two decades.

Conclusion: The current data provide further insight into the sensitivity of the 30-fold hERG margin 'cut-off' used for two decades. Using similar hERG assessments and these analyses, a future researcher can use a hERG margin threshold to support a negative QTc integrated risk assessment.