Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti‐seizure medication: Levetiracetam case study. Issue 1 (7th February 2023)

• Record Type: Journal Article
• Authors: Delaunois, Annie; Mathy, François‐Xavier; Cornet, Miranda; Gryshkova, Vitalina; Korlowski, Chloé; Bonfitto, François; Koch, Juliane; Schlit, Anne‐Françoise; Hebeisen, Simon; Passini, Elisa; Rodriguez, Blanca; Valentin, Jean‐Pierre
• Is Part Of: Pharmacology research & perspectives. Volume 11:Issue 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-07
• Subjects: cardiac safety -- CiPA -- ICH S7B -- levetiracetam -- nonclinical -- QT prolongation -- torsade de pointes; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.1059
• Languages: English
• ISSNs: 2052-1707

Abstract

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), NaV 1.5, CaV 1.2, Kir 2.1, KV 7.1/mink, KV 1.5, KV 4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large‐variability, and high‐risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV 7.1/mink at 7.5 mM, that is, 30‐fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10‐fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10‐fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors. Abstract : Levetiracetam (LEV) QT‐ogram illustrates that no biologically relevant changes (>10% or 10 ms) in QT‐related biomarkers occur up to 10‐ to 30‐fold its free therapeutic plasma concentration (FTPC) in core and follow‐up CiPA/S7B nonclinical assays, and the good concordance of this nonclinical dataset with clinical data (TQT study).