What question did this study set out to answer?

To evaluate the block potencies of five positive control drugs on the hERG channel under ICH E14/S7B best-practice guidelines, focusing on the effects of recording temperature and nonspecific drug loss.

July 2, 2022Journal of Pharmacological and Toxicological MethodsOpen Access

hERG block potencies for 5 positive control drugs obtained per ICH E14/S7B Q&As best practices: Impact of recording temperature and drug loss

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Why the study?

The new ICH E14/S7B Q&As guidelines allow hERG results to guide clinical decision-making, prompting evaluation of best-practice considerations including recording temperature and drug concentration verification using standard positive control drugs.

Population

Five positive control drugs (cisapride, dofetilide, terfenadine, sotalol, and E-4031) in manual whole cell patch clamp hERG assays

Comparison

Room temperature vs near physiological temperature, and real vs satellite concentration measurements

Design

In vitro electrophysiological study

Authors

CBClaudia Alvarez BaronUnited States Food and Drug Administration NTNicolas ThiebaudUnited States Food and Drug Administration MRMing RenUnited States Food and Drug Administration

Discussion

Member takes

Implication

Assay conditions warrant standardization in hERG testing; leaves open optimal parameters for clinical QT risk prediction.

Key Points

To evaluate the block potencies of five positive control drugs on the hERG channel under ICH E14/S7B best-practice guidelines, focusing on the effects of recording temperature and nonspecific drug loss.
Applied the manual whole-cell patch-clamp technique with an action potential-like voltage protocol at 0.2 Hz to test cisapride, dofetilide, terfenadine, sotalol, and E-4031.
Conducted electrophysiological recordings at room temperature and near-physiological temperature.
Quantified drug concentrations using fluid samples gathered during active patch-clamp recordings and parallel satellite experiments.
Recording temperature altered the blocking potency of E-4031, terfenadine, and sotalol, whereas cisapride and dofetilide potencies remained unaffected by temperature.
Cisapride and terfenadine experienced substantial drug loss caused by nonspecific binding to the perfusion equipment.
Potency estimates derived from satellite concentration measurements matched those from direct experimental sampling.

Structured PICO

Population

In vitro hERG assay using manual whole cell patch clamp method

Intervention

Cisapride, dofetilide, terfenadine, sotalol, and E-4031 tested at room and near physiological temperature

Outcome

hERG block potencies and concentration lossessurrogate

This study provides hERG block potencies for 5 positive control drugs and highlights the impact of temperature and nonspecific binding, supporting the new ICH E14/S7B Q&As best practices.

Cite This Study

Baron et al. (2022) studied this question.

synapsesocial.com/papers/6a72acd331a3df82432a35b5 https://doi.org/10.1016/j.vascn.2022.107193

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hERG block potencies for 5 positive control drugs obtained per ICH E14/S7B Q&As best practices: Impact of recording temperature and drug loss

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

hERG block potencies for 5 positive control drugs obtained per ICH E14/S7B Q&As best practices: Impact of recording temperature and drug loss

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Also Consider

Also Consider