Translation of flecainide- and mexiletine-induced cardiac sodium channel inhibition and ventricular conduction slowing from nonclinical models to clinical

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

“…In addition, some general anesthetics such as pentobarbital can affect cardiac conduction at anesthetic concentrations and may confound results. A recent study evaluated the value of several in vivo pre-clinical models to predict the cardiac sodium blocking risk in human (Heath et al, 2011). Translation of flecainide- or mexiletine-induced cardiac sodium channel inhibition and slowing of ventricular conduction from pre-clinical models to the clinic was assessed using conscious telemetered rat, dog, and anesthetized dog models.…”

“…A catheter-based clinical electrophysiology study may also be performed when a sodium channel blocker may be expected to elicit changes similar to those reported in non-rodent studies: prolongation of PR and/or QRS on the 12 lead ECG, and prolongation of the AH and/or HV intracardiac intervals. While studies have established a precedent for clinical evaluation of sodium channel blockers using invasive catheter studies (Heath et al, 2011), only limited data exist and do not clearly address when an invasive approach is warranted. Similarly, there are limited data available regarding the relative sensitivity and specificity of the PR, QRS, AH, and HV intervals when applied as biomarkers for hNav1.5 blockade.…”

Predicting QRS and PR interval prolongations in humans using nonclinical data

“…At this stage, in vitro Ca v /Na v studies may be conducted and the results (IC 50 ) obtained used, in the context with other data, to drive chemistry and select compounds to progress into in vivo studies. Later, in vivo investigations of drug‐induced CV effects, such as ECG intervals and haemodynamics, are typically conducted in anaesthetized and/or conscious rats, guinea pigs, dogs and non‐human primates (Heath et al , ; Cros et al , ; Erdemli et al , ; Marks et al , ), although rats are insensitive to hERG‐mediated effects (Mcdermott et al , ). During lead optimization, when a final candidate drug molecule is not yet selected, rodent CV studies may be conducted to evaluate the CV safety risks of a number of often structurally‐related molecules, alongside other testing such as efficacy studies.…”

“…Qualitative analyses have confirmed links between hNa v 1.5 inhibition, conduction in isolated rabbit heart tissue and QRS/PR prolongations in dogs and non‐human primates (Erdemli et al , ). Also, studies in conscious dog have identified and differentiated QRS effects of two anti‐arrhythmics (Heath et al , ). In this work, we wish to expand on this knowledge to investigate quantitative in vivo to clinical translations of QRS widening or PR prolongations, applying pharmacokinetic–pharmacodynamic (PKPD) and translational modelling.…”

Linking ryanodine receptor Ca2+leak and Na+current in heart: a day in the life of flecainide

“…It is interesting to note that the published ranges for the IC 50 of flecainide for RyR2 and Na V 1.5 are 2–7 μ m and 5–11 μ m respectively (Galimberti & Knollmann , Heath et al . ). With this in mind, experimentally differentiating between the substrate‐specific effects of flecainide in the intact physiological system poses substantial difficulties.…”