Abstract
Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.
Highlights
Chronic pain is a global health problem that affects an estimated 20.4% of adults worldwide with an addition 10% of newly diagnosed cases added each year [1]
TTX binds exclusively to voltage-gated sodium channel (VGSC) and as a result, it is the gold standard used by researchers for decades to characterize the structure and function of VGSCs including distinguishing between TTX-sensitive (TTX-IC50 ~10 nM) and TTX-resistant
One subject in control arm withdrew due to personal reasons prior to final dosing and their data was included in the moxifloxacin PK analysis
Summary
Chronic pain is a global health problem that affects an estimated 20.4% of adults worldwide with an addition 10% of newly diagnosed cases added each year [1]. The role of neuronal VGSCs in pain is well-established [2,3,4]. Toxins 2020, 12, 511 and non-selective VGSC blockers namely certain anticonvulsants, antidepressants, antiarrhythmics, and local anesthetics like lacosamide, carbamazepine, lidocaine, and mexiletine, have been shown to inhibit the ectopic discharges associated with pain [5,6]. These compounds can often have undesirable side effects, due most likely to their non-specific activity on more than one target channel or receptor. TTX binds exclusively to VGSCs and as a result, it is the gold standard used by researchers for decades to characterize the structure and function of VGSCs including distinguishing between TTX-sensitive (TTX-IC50 ~10 nM) and TTX-resistant
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