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.
Highlights
The ‘translational therapeutic index’ (TTI) is a drug’s ratio of nonclinical threshold dose for significant benefit versus threshold for adversity
The reason for this is that the benefit afforded by those drugs found to suppress sudden cardiac death (SCD) is offset by adverse drug reactions (ADRs); in some trials, mortality was increased[6,7,8] while in other trials attempts to minimise ADR risk by use of lower drug doses resulted in loss of effectiveness[9,10]
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
Summary
The ‘translational therapeutic index’ (TTI) is a drug’s ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. 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 stage in vivo work, with mexiletine’s TTI defining the gold standard that would need to be bettered. Available antiarrhythmic drugs have failed against SCD5 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 increased[6,7,8] while in other trials attempts to minimise ADR risk by use of lower drug doses resulted in loss of effectiveness[9,10]. A TTI can be defined as the ratio www.nature.com/scientificreports between the highest concentration without ADRs and the lowest concentration obtaining meaningful benefit, with a value of > 30 being deemed a minimum for most therapeutic scenarios[14]
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