2023 FDA Science Forum
A protocol to differentiate drug unbinding characteristics from cardiac sodium channel for proarrhythmia risk assessment
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- Center:
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Background:
Class I antiarrhythmic drugs (AADs) are sodium channel blockers that have been used to treat cardiac arrhythmias that arise through either abnormal automaticity or reentry. Class I AADs can be further classified into Class IA, IB and IC subgroups. Class IC AADs (flecainide or encainide) are associated with increased mortality in patients with structural heart diseases. Thus, identifying drug-sodium channel interaction characteristics to distinguish subgroups of Class I AAD is important for proarrhythmic risk assessment. Indeed, FDA recently issued notifications of Post-marketing Requirements for several antiepileptic drugs that are sodium channel blockers to request sponsors to characterize drug - sodium channel interaction characteristics for comparison with class I AADs.
Purpose:
There is no standardized protocol to characterize blocking kinetics of drug on cardiac sodium channels (NaV1.5). This creates an uncertainty and burden for regulatory reviews of such data, because electrophysiology results are dependent on protocols used. To enable a more efficient review process, this study aimed to test the utility of one protocol to characterize unbinding kinetics from cardiac NaV1.5 channel by classic IA (quinidine), IB (mexiletine) and IC (flecainide) AADs. Methodology: Whole cell recordings of NaV1.5 currents were made using overexpression cells. Channel properties, block potencies, and block kinetics of the aforementioned drugs were assessed at room temperature and near physiological temperature.
Results:
NaV1.5 peak current exhibited large magnitude, extremely fast activation and inactivation, and required a high degree of series resistance compensation to maintain adequate voltage control. Mexiletine, quinidine and flecainide showed fast, intermediate, and slow dissociation rates, respectively, at room temperature and near physiological temperature. Both association and dissociation rates of the three drugs increased by 3~5-times at physiological temperature compared with at room temperature. However, the potencies of the three drugs on NaV1.5 current were not impacted by recording temperature.
Conclusion:
The dissociation time constants of quinidine, mexiletine and flecainide as determined using this protocol are consistent with their classification in the Class IA, IB, and IC subgroups. Adoption of this protocol for proarrhythmia risk assessment based on drug-cardiac sodium channel interactions should facilitate the review process of drugs with sodium channel blockade.
