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

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...

Full description

Saved in:
Bibliographic Details
Published in:Pharmacology research & perspectives 2023-02, Vol.11 (1), p.e01059-n/a
Main 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
Format: Article
Language:English
Subjects:
Animals
Automation
Biomarkers
cardiac safety
Cardiomyocytes
CiPA
Convulsions & seizures
Dogs
Experiments
Humans
ICH S7B
Induced Pluripotent Stem Cells
levetiracetam
Levetiracetam - pharmacology
Long QT Syndrome
Myocytes, Cardiac
nonclinical
Original
Ovaries
Pharmacology
QT prolongation
Simulation
Stem cells
torsade de pointes
Variance analysis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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), NaV1.5, CaV1.2, Kir2.1, KV7.1/mink, KV1.5, KV4.3, 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% 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).
ISSN:2052-1707
2052-1707
DOI:10.1002/prp2.1059