Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults
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 twe...
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| Veröffentlicht in: | Toxins 2020-08, Vol.12 (8), p.511, Article 511 |
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| description | 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 mu g, 30 mu g, and 45 mu g TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (C-max) within 1.5 h. Both extent of exposure (AUC) and C(max)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 (Delta Delta QTcF) 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. |
| doi_str_mv | 10.3390/toxins12080511 |
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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 mu g, 30 mu g, and 45 mu g TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (C-max) within 1.5 h. Both extent of exposure (AUC) and C(max)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 (Delta Delta QTcF) 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.</description><identifier>ISSN: 2072-6651</identifier><identifier>EISSN: 2072-6651</identifier><identifier>DOI: 10.3390/toxins12080511</identifier><identifier>PMID: 32784930</identifier><language>eng</language><publisher>BASEL: Mdpi</publisher><subject>Adolescent ; Adult ; Adults ; analgesic ; Analgesics ; Cardiac arrhythmia ; Chronic pain ; Clinical trials ; Confidence intervals ; Double-Blind Method ; ECG ; Electrocardiography ; Evaluation ; FDA approval ; Female ; Food Science & Technology ; Headache ; Heart rate ; Heart Rate - drug effects ; Humans ; Injections, Subcutaneous ; Liability ; Life Sciences & Biomedicine ; Long QT Syndrome ; Male ; Middle Aged ; Moxifloxacin ; Myalgia ; Nausea ; Pain ; Paresthesia ; Pharmacokinetics ; Plasma ; Prolongation ; QT interval ; Randomization ; Respiratory system ; Safety ; Science & Technology ; Sodium channels (voltage-gated) ; Tetrodotoxin ; Tetrodotoxin - administration & dosage ; Tetrodotoxin - adverse effects ; Tetrodotoxin - blood ; Tetrodotoxin - pharmacokinetics ; Toxicology ; Upper bounds ; voltage-gated sodium channels ; Young Adult</subject><ispartof>Toxins, 2020-08, Vol.12 (8), p.511, Article 511</ispartof><rights>2020. 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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 mu g, 30 mu g, and 45 mu g TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (C-max) within 1.5 h. Both extent of exposure (AUC) and C(max)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 (Delta Delta QTcF) 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.</abstract><cop>BASEL</cop><pub>Mdpi</pub><pmid>32784930</pmid><doi>10.3390/toxins12080511</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0002-8518-8895</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Adult Adults analgesic Analgesics Cardiac arrhythmia Chronic pain Clinical trials Confidence intervals Double-Blind Method ECG Electrocardiography Evaluation FDA approval Female Food Science & Technology Headache Heart rate Heart Rate - drug effects Humans Injections, Subcutaneous Liability Life Sciences & Biomedicine Long QT Syndrome Male Middle Aged Moxifloxacin Myalgia Nausea Pain Paresthesia Pharmacokinetics Plasma Prolongation QT interval Randomization Respiratory system Safety Science & Technology Sodium channels (voltage-gated) Tetrodotoxin Tetrodotoxin - administration & dosage Tetrodotoxin - adverse effects Tetrodotoxin - blood Tetrodotoxin - pharmacokinetics Toxicology Upper bounds voltage-gated sodium channels Young Adult |
| title | Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults |
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