Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti-seizure medication: Levetiracetam case study.

ABSTRACT: Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to "pressure test" the CiPA approach with LEV and check the concordance of nonclinical core and follow-up S7B assays with clinical and post-marketing data. The following experiments were conducted with LEV (0.25-7.5 mM): patch clamp assays on hERG (acute or trafficking effects), Na_V 1.5, Ca_V 1.2, K_ir 2.1, K_V 7.1/mink, K_V 1.5, K_V 4.3, and HCN4; in silico electrophysiology modeling (Vi

SUBMITTER: Delaunois A 

PROVIDER: S-EPMC9903303 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature