{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:24:47Z","timestamp":1788459887384,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T00:00:00Z","timestamp":1766275200000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The Comprehensive in\u00a0vitro Proarrhythmia Assay (CiPA) initiative proposes integrating multi\u2010cardiac ion channel pharmacology to improve the prediction of drug\u2010induced\n                    <jats:italic>Torsade de Pointes<\/jats:italic>\n                    (TdP) risk. However, several studies under CiPA have demonstrated misalignment between nonclinical and clinical data. One study showed ECG changes induced by chloroquine, lopinavir, and ritonavir suggestive of Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 and Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 channel block. However, ion channel data used to design the clinical study showed no such interactions. Another study reported TdP cases in patients treated with vanoxerine, a drug with literature data demonstrating similar block potencies for hERG and Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 channels suggesting lower TdP risk than selective hERG blockers. Finally, astemizole, risperidone, and clarithromycin\u2014\u201cintermediate TdP risk\u201d CiPA drugs\u2014were reported to have hERG\u2010active metabolites, yet hERG data for metabolites were not integrated when developing in silico human myocyte models for risk prediction. To increase the confidence of using nonclinical data in regulatory decision\u2010making, the sources of these inconsistent nonclinical\u2010clinical findings and data gap for metabolites need to be addressed. Here the effects of chloroquine, lopinavir, ritonavir, and vanoxerine on hERG, Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2, and\/or Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 channels were studied using protocols consistent with ICH S7B Q&amp;A 2.1 best practices. hERG block potencies for astemizole, risperidone, clarithromycin plus their major metabolites were also determined. The results showed improved alignment between ion channel block profiles and drug\u2010induced ECG changes and proarrhythmia, underscoring the importance of using physiologically relevant experimental protocols, accounting for ion channel\u2010active metabolites, and continuing to build the knowledge base of arrhythmogenesis mechanisms. Data may be found at:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/osf.io\/7rfua\/\">https:\/\/osf.io\/7rfua\/<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1111\/cts.70451","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T05:31:30Z","timestamp":1766381490000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reassessing the Conduct of Patch Clamp Cardiac Ion Channel Assays to Improve Nonclinical Data Translation to Clinical\n                    <scp>ECG<\/scp>\n                    Changes and Proarrythmia Risk"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4352-6603","authenticated-orcid":false,"given":"Claudia","family":"Alvarez Baron","sequence":"first","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical 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