Cardiosafety Testing Based on CiPA - at Scale with SyncroPatch 384 and Genedata Screener
SLAS2022, Boston, MA, USA
February 7, 2022
In the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative, FDA and other medicines agencies collaborate with pharma companies, academics, CROs, and device companies towards a more comprehensive and robust, mechanism-based in-vitro assessment of arrhythmia risk for new drugs. The CiPA protocols consist of panels of standardized in-vitro assays, incorporating defined tests against major cardiac ion channels, and thus enable large-scale, early discovery screens for liability prediction1. Here we present a tailored solution for upscaled and traceable cardiac safety studies performed according to the CiPA guidelines.
A combination of automated patch clamp assays run on Nanion SyncroPatch 384 instruments with automatic processing of the resulting data in the Genedata Screener software enables comprehensive cardiac risk assessment on possibly thousands of compounds per week following CiPA experimental and analysis guidelines. The integrated, efficient workflow enables collection of high-quality electrophysiological data, their rigorous analysis and their collation with non-APC assays (e.g. impedance data) for final panel assessment. We show this on hERG and Nav1.5 assays conducted in compliance with CiPA recommendations on experimental procedures2-4. Data processing, use of control data, data normalization, visualization of recording quality over time and other quality control metrics, assay end results and cross-assay safety scores are all combined in a result package that provides a clear path for putative submission to regulatory authorities. The automation technology presented enables large-scale cardiac safety assessment of candidate molecules, comprehensive in its quality and dimensionality, authoritative by its data integrity and accessibility, to eliminate risks earlier in the process of therapeutic development.
- Cavero & Holzgrefe. “Comprehensive in vitro Proarrhythmia Assay, a novel in vitro/in silico paradigm to detect ventricular proarrhythmic liability: a visionary 21st century initiative.” Expert Opin. Drug Saf. 13(6):745-758 (2014).
- E14/S7B Draft Q&As (Aug 2020) database.ich.org/sites/default/files/ICH_E14-S7B_QAs_Step2_2020_0827_0.pdf
- Brinkwirth N, Takasuna K, Doi M, Becker N, Obergrussberger A, Friis S, Furukawa H, Hasegawa Y, Oka T, Ohtsuki A, Fertig N, Stoelzle-Feix S. Reliable identification of cardiac liability in drug discovery using automated patch clamp: Benchmarking best practices and calibration standards for improved proarrhythmic assessment. J Pharmacol Toxicol Methods. 2020 Sep;105:106884. doi: 10.1016/j.vascn.2020.106884. Epub 2020 Jun 18. PMID: 32565325.
- Rotordam MG, Obergrussberger A, Brinkwirth N, Takasuna K, Becker N, Horváth A, Goetze TA, Rapedius M, Furukawa H, Hasegawa Y, Oka T, Fertig N, Stoelzle-Feix S. Reliable identification of cardiac conduction abnormalities in drug discovery using automated patch clamp II: Best practices for Nav1.5 peak current in a high throughput screening environment. J Pharmacol Toxicol Methods. 2021 Nov-Dec;112:107125. doi: 10.1016/j.vascn.2021.107125. Epub 2021 Sep 6. PMID: 34500078.