Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart

Abstract

the 'translational therapeutic index' (tti) is a drug's ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. In early nonclinical research, discovery and safety studies are normally undertaken separately. our aim was to evaluate a novel integrated approach for generating a tti for drugs intended for prevention of ischaemia-induced ventricular fibrillation (VF). We templated the current best available class 1b antiarrhythmic, mexiletine, using the rat Langendorff preparation. Mexiletine's beneficial effects on the incidence of VF caused by 120 min regional ischaemia were contrasted with its concurrent adverse effects (on several variables) in the same hearts, to generate a TTI. Mexiletine 0.1 and 0.5 µM had no adverse effects, but did not reduce VF incidence. Mexiletine 1 µM reduced VF incidence to 0% but had adverse effects on atrioventricular conduction and ventricular repolarization. Separate studies undertaken using an intraventricular balloon revealed no detrimental effects of mexiletine (1 and 5 µM) on mechanical function, or any benefit against reperfusion-related dysfunction. Mexiletine's TTI was found to be less than two, which accords with its clinical therapeutic index. Although non-cardiac adversity, identifiable from additional in vivo studies, may reduce the tti further, it cannot increase it. our experimental approach represents a useful early-stage integrated risk/benefit method that, when TTI is found to be low, would eliminate unsuitable class 1b drugs prior to next stage in vivo work, with mexiletine's tti defining the gold standard that would need to be bettered. Coronary heart disease and acute myocardial infarction (AMI) constitute the largest cause of death worldwide 1 with sudden cardiac death (SCD) responsible for approximately 50% of lethality 2,3. Most SCD is due to ischaemia-induced arrhythmias, particularly ventricular fibrillation (VF) and ventricular tachycardia 4. Currently available antiarrhythmic drugs have failed against SCD 5. The reason for this is that the benefit afforded by those drugs found to suppress SCD is offset by adverse drug reactions (ADRs); in some trials, mortality was actually increased 6-8 while in other trials attempts to minimise ADR risk by use of lower drug doses resulted in loss of effectiveness 9,10. Presently the class 1b antiarrhythmic, mexiletine, and the non-selective class III drug, amiodarone 11 , are the only antiarrhythmics prescribed for SCD outside the hospital setting, but even these drugs are not considered sufficiently efficacious for use in the larger lower-risk populations 5,12 leaving a huge and longstanding unmet therapeutic need 4. Since amiodarone is an anomalous example of a class (III) that is otherwise discounted as a solution to SCD owing to proarrhythmia 5,12 , this leaves only class 1b agents as an avenue for new drug development. An essential part of the process of any new drug development is to mitigate against ADRs during the nonclinical phase. In view of this, we and oth...

OCT2013, an ischaemia‐activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine

“…OCT2013 is a first-in-class antiarrhythmic prodrug, with ischaemiaselective actions that mimic those of lidocaine, resulting in VF prevention, but without adversity at ≥16 times the effective dose in vivo and ≥7 the effective concentration in vitro (these numbers representing the translational therapeutic index in each setting). This is far better than the profile of lidocaine, whose equivalent value was <1 according to the data in the present study, and another clinically used class 1b drug, mexiletine (value < 2 according to recent data derived from the in vitro rat heart model used in the present study; Hesketh et al, 2020). There are no drugs tested in animal models of sudden cardiac death that have shown a profile as promising as that of OCT2013 since assessment began in the 1960s, to our knowledge.…”

“…The relabelled stock solutions were used by the operator to prepare solutions for experimentation, guided by a randomisation table (prepared separately) (Curtis et al, 2013). A test solution or other intervention was selected by reference to the randomisation table . Blinding was maintained until after data had been collected, collated and analysed, and any excluded preparations or animals had been replaced according to predetermined exclusion criteria (Hesketh et al, 2020). Investigational endpoints were all determined prior to the start of each study.…”