{"id":6486,"date":"2023-02-17T07:13:56","date_gmt":"2023-02-17T07:13:56","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2021-applying-the-cipa-approach-to-evaluate-cardiac-proarrhythmia-risk-of-some-antimalarials-used-off%e2%80%90label-in-the-first-wave-of-covid%e2%80%9019\/"},"modified":"2023-02-17T07:13:56","modified_gmt":"2023-02-17T07:13:56","slug":"2021-applying-the-cipa-approach-to-evaluate-cardiac-proarrhythmia-risk-of-some-antimalarials-used-off%e2%80%90label-in-the-first-wave-of-covid%e2%80%9019","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2021-applying-the-cipa-approach-to-evaluate-cardiac-proarrhythmia-risk-of-some-antimalarials-used-off%e2%80%90label-in-the-first-wave-of-covid%e2%80%9019\/","title":{"rendered":"2021 &#8211; Applying the CiPA Approach to Evaluate Cardiac Proarrhythmia Risk of some Antimalarials Used Off\u2010label in the First Wave of COVID\u201019"},"content":{"rendered":"<p>We applied a set of\u00a0in silico\u00a0and\u00a0in vitro\u00a0assays, compliant with the CiPA (Comprehensive In Vitro Proarrhythmia Assay) paradigm, to assess the risk of chloroquine or hydroxychloroquine\u2010mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVID\u201019. Each drug or drug combination was tested in patch clamp assays on 7 cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay\u00ae) using control (healthy) or high\u2010risk cell populations, and in human induced pluripotent stem cell (hiPSC)\u2010derived cardiomyocytes. In each assay, concentration\u2010response curves encompassing and exceeding therapeutic free plasma levels were generated. Both chloroquine and hydroxychloroquine showed blocking activity against some potassium, sodium and calcium currents. Chloroquine and hydroxychloroquine inhibited I<sup>Kr<\/sup>\u00a0(IC<sub>50<\/sub>: 1\u00b5M and 3\u20107 \u00b5M, respectively) and IK1\u00a0currents (IC<sub>50<\/sub>: 5 and 44 \u00b5M, respectively). When combining hydroxychloroquine with azithromycin, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC<sub>50<\/sub>\u00a0> 300 \u2010 1000\u00b5M). Using Virtual Assay\u00ae, both antimalarials affected several TdP indicators, chloroquine being more potent than hydroxychloroquine. Effects were more pronounced in the high\u2010risk cell population. In hiPSC\u2010derived cardiomyocytes, all drugs showed early\u2010after\u2010depolarizations, except azithromycin. Combining chloroquine or hydroxychloroquine with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or off\u2010label use in COVID\u201019, chloroquine and hydroxychloroquine use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[54,109],"target_categories":[61],"target_families":[333],"targets":[92],"resource_keyword":[],"class_list":["post-6486","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","therapeutic_areas-cardiac-safety-cipa","therapeutic_areas-respiratory-diseases","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv11-1-herg"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/6486","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=6486"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=6486"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=6486"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=6486"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=6486"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=6486"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=6486"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=6486"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=6486"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}