Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults

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.

Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial

“…Another patient in the TTX 30 µg QD cohort experienced mild QT prolongation that was unchanged from baseline ( Table S2 ). A study completed in healthy adults has demonstrated that exposure up to TTX 45 µg QD (corresponding to higher TTX plasma blood C max than 30 µg BID) does not cause blood pressure or ECG changes as determined by concentration-QTc analysis [ 38 ].…”

“…TTX is a specific blocker of VGSCs with high affinity for TTX-sensitive VGSCs found in peripheral nerves. Like other toxins used in medicine (e.g., botulinum toxin type A, morphine, curare), therapeutic doses of TTX are safe and well-tolerated [ 38 ]. As a peripherally acting, non-addictive analgesic targeting TTX-sensitive VGSCs, TTX is a rational candidate for patients with inadequately controlled CINP.…”

“…This pain relief observed beyond week 1 post-treatment occurred in the absence of any residual systemic TTX. Prior pharmacokinetic analysis has revealed TTX has a t 1/2 of approximately 4.5 h and is almost exclusively eliminated (approximately 96.75% of dose) within 36 h [ 38 ]. The absence beyond week 1 of any AEs associated with TTX such as hypoesthesia, oral hypoesthesia, paresthesia, and oral paresthesia also support the lack of residual systemic TTX as the cause of the observed long-duration pain relief.…”

Voltage-Gated Sodium Channels: A Prominent Target of Marine Toxins

“…Additionally, all doses demonstrated an absence of any clinically significant toxicity. Up to 45 μg of TTX was found safe and tolerated in terms of cardiac safety [ 43 ]. Like any other toxin, TTX may present some limitations such as the low efficacy of diffusion through diverse tissue barriers to the site of action, which means that the blockage of NaV will also be limited [ 44 ].…”

Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?

“…Recently, Wex Pharmaceutical Inc. has published the results of a phase 1 dose escalation study that was performed to evaluate the safety, tolerability, and pharmacokinetics of TTX at clinically relevant exposures in healthy volunteers [ 85 ]. In this randomized, double-blind, placebo-controlled study, all safety appraisals show that TTX is safe, well-tolerated, and does not cause cardiac alterations of clinical or regulatory concern or induce any clinically measurable impairment in neuromuscular or respiratory system.…”