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

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). AbstractLevetiracetam (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%) of hERG and KV7.1/mink at 7.5  mM, that i...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research