Analysis of torsadogenic and pharmacokinetic profile of E-4031 in dogs bridging the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects

Abstract

We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

“…We also assessed the effect of the hERG-type K + channel blocker E4031, which is an anti-arrhythmic drug. However, this drug is pro-arrhythmic in vitro especially at higher doses (Goto et al, 2018). As expected, following treatment with the E4031, a significant increase in the beat period and FPDc was observed in the 2D cultures following treatment with 50 and 100 nM of E4031, while a significant increase was observed in 3D cultures only after treatment with 100 nM E4031 ( Figures 7C-E).…”

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart

“…The left ventricular wall mass was calculated using IVSd, LVPWTd and LVIDd of the echocardiography, which was 11.4 g for the chronic atrioventricular block monkey heart at 7 months ( Figure 2 ), 75.4 g for the chronic atrioventricular block canine heart ( Takahara et al, 2007 ), 179.3 g for the normal human adult heart ( Feigenbaum, 1986 ) and 3.6 g for the intact male New Zealand white rabbit heart ( Fontes-Sousa et al, 2006 ). Meanwhile, the frequency of TdP wave for those was estimated to be 2–5 Hz for the chronic atrioventricular block monkey heart ( Goto et al, 2020a ; Goto et al, 2020b ; Goto et al, 2021 ), 5–6 Hz for the chronic atrioventricular block canine heart ( Izumi-Nakaseko et al, 2017 ; Goto et al, 2018 ; Goto et al, 2019a ; Goto et al, 2019b ), 3–4.5 Hz for the human adult heart ( Rosso et al, 2021 ) and 3–6 Hz for the acute atrioventricular block rabbit heart ( Hagiwara et al, 2017 ), respectively. As a results, I was calculated to be 4.5–11.2 for the chronic atrioventricular block monkey heart, 21.1–25.3 for the chronic atrioventricular block canine heart, 17.2–25.4 for the normal human adult heart and 4.6–9.2 for the intact male New Zealand white rabbit heart.…”