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Article

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

by
Mojgan Kavoosi
1,*,
Terry E. O’Reilly
2,
Mehran Kavoosi
1,
Peng Chai
3,
Caroline Engel
4,
Walter Korz
1,
Christopher C. Gallen
1 and
Robert M. Lester
2
1
WEX Pharmaceuticals Inc., Vancouver, BC V6E-4A6, Canada
2
Celerion Inc., Tempe, AZ 85283, USA
3
Celerion Inc., Lincoln, NE 68502, USA
4
Celerion Inc., Montreal, QC H4M-2P1, Canada
*
Author to whom correspondence should be addressed.
Toxins 2020, 12(8), 511; https://doi.org/10.3390/toxins12080511
Submission received: 7 July 2020 / Revised: 5 August 2020 / Accepted: 5 August 2020 / Published: 9 August 2020
(This article belongs to the Special Issue Tetrodotoxin (TTX) as a Therapeutic Agent)
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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.
Keywords: tetrodotoxin; pain; analgesic; QT interval; ECG; voltage-gated sodium channels; clinical trial; neuropathy; toxicity; safety tetrodotoxin; pain; analgesic; QT interval; ECG; voltage-gated sodium channels; clinical trial; neuropathy; toxicity; safety

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MDPI and ACS Style

Kavoosi, M.; O’Reilly, T.E.; Kavoosi, M.; Chai, P.; Engel, C.; Korz, W.; Gallen, C.C.; Lester, R.M. Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults. Toxins 2020, 12, 511. https://doi.org/10.3390/toxins12080511

AMA Style

Kavoosi M, O’Reilly TE, Kavoosi M, Chai P, Engel C, Korz W, Gallen CC, Lester RM. Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults. Toxins. 2020; 12(8):511. https://doi.org/10.3390/toxins12080511

Chicago/Turabian Style

Kavoosi, Mojgan, Terry E. O’Reilly, Mehran Kavoosi, Peng Chai, Caroline Engel, Walter Korz, Christopher C. Gallen, and Robert M. Lester. 2020. "Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults" Toxins 12, no. 8: 511. https://doi.org/10.3390/toxins12080511

APA Style

Kavoosi, M., O’Reilly, T. E., Kavoosi, M., Chai, P., Engel, C., Korz, W., Gallen, C. C., & Lester, R. M. (2020). Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults. Toxins, 12(8), 511. https://doi.org/10.3390/toxins12080511

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