[Background] In vitro hERG channel inhibition assays, in vivo electrocardiogram assays using conscious animals, and various types of studies are currently performed for predicting drug-induced torsade de pointes (TdP) in drug safety evaluation based on ICH S7B guidelines. In addition, best practice of in vitro hERG assay was presented in ICH S7B Q & A Section 2.1 in Feb. 2022 to support an integrated risk assessment of the potential of drugs that induce Tdp and/or other types of arrhythmias. The best practice recommends that in vitro hERG assays are performed at physiological temperature instead of room temperature, which has been widely used.
Therefore, we performed in vitro hERG assays using a protocol that has been conducted in safety pharmacology studies and using a protocol that refers to the best practice to evaluate differences in drug reactivity between these methods.
[Methods and results] In the best practice, we conducted experiments at room or physiological temperature using the ramp down voltage protocol in reference to the CiPA protocol (Jul. 30, 2021). In the conventional method, we conducted experiments at room temperature using the step voltage protocol.
We will report the results of comparison between various experimental conditions regarding the IC50 and hill coefficients of compounds reported to have temperature dependence on drug reactivity and those reported to have Tdp risk.
